Diaminothiazoles having antiproliferative activity

ABSTRACT

Disclosed are novel diaminothiazoles of formula                    
     wherein R 1 , R 2 , R 3 , R 4  and R 5  are as herein disclosed. These compounds and their pharmaceutically acceptable salts and esters are selective inhibitors of Cdk4. As such, these compounds and their pharmaceutically acceptable salts and esters are anti-proliferative agents useful in the treatment or control of solid tumors, in particular breast, colon, lung and prostate tumors. Also disclosed are pharmaceutical compositions containing the compounds of formula I and their pharmaceutically acceptable salts and esters, as well as intermediates useful in the preparation of the compounds of formula I.

The priority of U.S. Provisional Application Nos. 60/263,315, filed onJan. 22, 2001 and 60/326,807, filed Oct. 3, 2001, is claimed.

FIELD OF THE INVENTION

The present invention is directed to novel diaminothiazoles of formula

These compounds inhibit cyclin-dependent kinase 4 (Cdk4) and areselective against Cdk2 and Cdk1. These compounds and theirpharmaceutically acceptable salts and esters have antiproliferativeactivity and are useful in the treatment or control of cancer, inparticular solid tumors. This invention is also directed topharmaceutical compositions containing such compounds and to methods oftreating or controlling cancer, most particularly the treatment orcontrol of breast, lung and colon and prostate tumors. Finally, thisinvention is also directed to novel intermediate compounds useful in thepreparation of a compound of formula I.

BACKGROUND OF THE INVENTION

Uncontrolled cell proliferation is the hallmark of cancer. Canceroustumor cells typically have some form of damage to the genes thatdirectly or indirectly regulate the cell-division cycle.

The progression of cells through the various phases of the cell cycle isregulated by a series of multienzyme complexes consisting of aregulatory protein, a cyclin, and a kinase. These kinases are calledcyclin-dependent kinases (Cdks). The Cdks are expressed throughout thecell cycle, while the levels of the cyclins vary depending on the stageof the cell cycle.

The transition from G₁ phase into S phase is regulated by the complex ofCdk4 with cyclin D. This complex phosphorylates the tumor supressorprotein Retinoblastoma (pRb), releasing the transcription factor E2F andallowing the expression of genes required in S phase (Nevins, J. R.Science 1992, 258, 424-429). Blocking the activity of the Cdk4/cyclin Dcomplex arrests the cell cycle in G₁ phase. For example, the proteins ofthe INK4 family, including p16^(INK4a), which block the kinase activityof the Cdk4/cyclin D complex, cause arrest in G₁ (Sherr, C. J. Science1996, 274, 1672-1677).

Recent experiments show that the complex of Cdk4 with cyclin D3 alsoplays a role in cell cycle progression through G₂ phase. Inhibition ofthis complex, either by p16 or using a dominant negative Cdk4, resultsin arrest in G₂ phase in cells that do not express pRb (Gabrielli B. G.et al. J. Biol. Chem. 1999, 274, 13961-13969).

Numerous defects in the pRb pathway have been shown to be involved invarious cancers. For example, overexpression of Cdk4 has been observedin cases of hereditary melanoma (Webster, K. R. Exp. Opin. Invest. Drugs1998, 7, 865-887); cyclin D is overexpressed in many human cancers(Sherr, C. J. Science 1996, 274, 1672-1677); p16 is mutated or deletedin many tumors (Webster, K. R. Exp. Opin. Invest Drugs 1998, 7,865-887); and pRb function is lost through mutation or deletion in manyhuman cancers (Weinberg, R. A. Cell 1995, 81, 323-330). Defects in thispathway have also been shown to have an effect on prognosis. Forexample, loss of p16 is correlated with poor prognosis in non-small-celllung carcinoma (NSCLC) and malignant melanoma (Tsihlias, J. et al. Annu.Rev. Med. 1999, 50, 401-423).

Because of the involvement of the Cdk4/cyclin D/pRb pathway in humancancer through its role in regulating progression of the cell cycle fromG₁ to S phase, and the potential therapeutic benefit from modulatingthis pathway, there has been considerable interest in agents thatinhibit or promote elements of this pathway. For example, effects oncancer cells have been shown using antibodies, antisenseoligonucleotides and overexpression or addition of proteins involved inthe pathway. See, e.g., Lukas, J. et al. Nature 1995, 79, 573-582;Nevins, J. R. Science 1992, 258, 424-429; Lim, I. K. et al. MolecularCarcinogenesis 1998, 23, 25-35; Tam, S. W. et al. Oncogene 1994, 9,2663-2674; Driscoll, B. et al. Am. J. Physiol. 1997, 273 (Lung Cell.Mol. Physiol.), L941-L949; and Sang, J. et al. Chin. Sci. Bull. 1999,44, 541-544). There is thus an extensive body of literature validatingthe use of compounds inhibiting targets in the Cdk4 pathway asanti-proliferative therapeutic agents.

It is thus desirable to identify chemical inhibitors of Cdk4 kinaseactivity. It is particularly desirable to identify small moleculecompounds that may be readily synthesized and are effective ininhibiting Cdk4 or Cdk4/cyclin complexes, for treating one or more typesof tumors.

There are several examples of small molecule inhibitors of thecyclin-dependent kinases, including Cdk4 (Rosania, G. R. et al. Exp.Opin. Ther. Patents 2000, 10, 215-230). Several of these compoundsinhibit multiple targets.

For example, Flavopiridol (Aventis)

is in Phase II clinical trials for lymphoma and multiple myeloma andalso for the treatment of solid tumors. It inhibits Cdk1, Cdk2 and Cdk4and it blocks cells in both G1 and G2 phases. It is also a weakerinhibitor of PKC and EGFR (Senderowicz, A. M. et al. J. Natl. CancerInst 2000, 92, 376-387).

WO9716447 (Mitotix) discloses the following compounds related toflavopiridol

Some of these compounds are stated to inhibit Cdk4.

WO9943675 and WO9943676 (Hoechst) disclose the following purinederivatives

which are stated to inhibit Cdk2 and Cdk4.

WO9833798 (Warner-Lambert) discloses the following pyridopyrimidines

These compounds are stated to inhibit the cyclin dependent kinases Cdk1,Cdk2, and Cdk4. Some of these compounds also inhibit the receptortyrosine kinases PDGFR and EGFR, and the cellular Src protein kinase,c-Src.

WO9909030 (Warner-Lambert) discloses naphthyridinones

that inhibit PDGFR, FGFR, c-Src, and the cyclin dependent kinases Cdk1,Cdk2, and Cdk4.

WO0039101 (AstraZeneca) discloses diaminopyrimidines

that inhibit Cdk4 and FAK3.

WO0012485 (Zeneca) discloses diaminopyrimidines

that inhibit Cdk4 and FAK3.

WO9924416 (Bristol-Myers Squibb) discloses aminothiazole inhibitors offormula

The compounds inhibit Cdk1, Cdk2 and Cdk4.

WO9921845 (Agouron) discloses diaminothiazole inhibitors of Cdk1, Cdk2and Cdk4, having the following structure

where R1 and R2 are ring systems. This patent application indicates thatin cases where the R² ring system does not bear an ortho substituent,the compounds lack potency and selectivity as inhibitors of Cdk4.

Finally, WO0075120 (Agouron) discloses diaminothiazole inhibitors ofprotein kinases including VEGF-R, FGF-R, CDK complexes, TEK, CHK1, LCK,and FAK, having the following structure

It is desirable to provide small molecule inhibitors of Cdk4 that areselective against other Cdks. That is, the small molecule issignificantly more inhibitory (at least 10 times, preferably 100 times)of Cdk4 than Cdk1 and Cdk2. This parameter is desirable because of thepotential concomitant toxicity and other undesirable complications thatmay follow from inhibiting multiple targets. Thus, for purposes of thisinvention, the inhibition of Cdk2 and Cdk1 are monitored to determinethe selectivity of the inhibition of Cdk4. A compound that exhibitsselectivity against Cdk2 and Cdk1 is expected to have a better safetyprofile than a compound that is not selective between Cdk4, Cdk2 andCdk1.

There continues to be a need for easily synthesized, small moleculecompounds that are specific inhibitors of Cdk4 for the treatment orcontrol of one or more types of solid tumors. It is an object of thisinvention to provide such compounds, compositions containing suchcompounds, and methods of using such compounds in the treatment orcontrol of breast, colon, lung and prostate tumors.

SUMMARY OF THE INVENTION

The present invention is directed to novel diaminothiazoles capable ofselectively inhibiting the activity of Cdk4. These compounds are usefulin the treatment or control of cancer, in particular the treatment orcontrol of solid tumors. In particular this invention is directed to acompound of formula

or the pharmaceutically acceptable salts or esters thereof, wherein

R¹ is selected from the group consisting of

H,

lower alkyl that optionally may be substituted with a group selectedfrom OR⁶, cycloalkyl, and NR⁷R⁸,

cycloalkyl,

COR⁹, and

SO₂R¹⁰;

R² is selected from the group consisting of

H,

F,

Cl, and

CH₃;

R³, R⁴ and R⁵ are each independently selected from the group consistingof

H,

lower alkyl, which optionally may be substituted with a group selectedfrom OR⁶ and NR⁷R⁸,

OR¹¹,

NR¹²R¹³,

halogen,

NO₂,

CONR⁶R⁹,

NHSO₂R¹⁴,

CN,

S-lower alkyl,

OCF₃, and

OCHF₂,

or alternatively, R³ and R⁴ taken together with the two carbons and thebond between them from the benzene ring (D) to which R³ and R⁴ areattached can form a ring system having up to two additional rings, eachof said rings

having 5-7 atoms, and the ring attached to the benzene ring (D)optionally including one or more hetero atoms and being optionallysubstituted by lower alkyl,

provided that R³ and R⁴ are not simultaneously —OCH₃, and providedfurther that R⁴ is not —Cl when R³ is —NO₂;

R⁶ and R⁹ are independently selected from the group consisting of

H, and

lower alkyl that optionally may be substituted by OH and halogen;

R⁷ and R⁸ are independently selected from the group consisting of

H, and

lower alkyl that optionally may be substituted by OR⁶,

or, alternatively, R⁷ is H and R⁸ is OH,

or, alternatively, NR⁷R⁸ can optionally form a ring having 5-6 atoms,said ring optionally including one or more additional hetero atoms andbeing optionally substituted by the group consisting of one or more ofOR⁶ and lower alkyl which itself may be optionally substituted by OH;

R¹⁰ is selected from the group consisting of

lower alkyl which optionally may be substituted by one or more chlorineor fluorine, and

NH₂;

R¹¹ is selected from the group consisting of

H, and

lower alkyl that optionally may be substituted by OR⁶, COOH, halogen andNR¹⁵R¹⁶;

R¹² and R¹³ are independently selected from the group consisting of

H,

lower alkyl that optionally may be substituted with a group selectedfrom OR⁶, COOH and NR¹⁵R¹⁶,

COR¹⁷, and

SO₂R¹⁸,

provided that only one of R¹² and R¹³ is COR¹⁷ or SO₂R¹⁸,

or alternatively NR¹²R¹³ can optionally form a ring having 5-6 atoms,said ring optionally including one or more additional hetero atoms andbeing optionally substituted by the group consisting of one or more ofOR⁶ and lower alkyl which itself may be optionally substituted by OH;

R¹⁴ is lower alkyl;

R¹⁵ and R¹⁶ are independently selected from the group consisting of

H, and

lower alkyl that optionally may be substituted by OH,

or alternatively NR¹⁵R¹⁶ can optionally form a ring having 5-6 atoms,said ring optionally including one or more additional hetero atoms andbeing optionally substituted by the group consisting of one or more ofOR⁶ and lower alkyl which itself may be optionally substituted by OH;

R¹⁷ is selected from the group consisting of

H, and

lower alkyl which optionally may be substituted by OH, COOH and NR¹⁵R¹⁶;and

R¹⁸ is lower alkyl.

The present invention is also directed to pharmaceutical compositionscomprising a therapeutically effective amount of one or more compoundsof formula I and a pharmaceutically acceptable carrier or excipient.

The present invention is further directed to a method for treating solidtumor, in particular breast or colon tumors, by administering to a humanpatient in need of such therapy an effective amount of a compound offormula I, its salt and/or ester.

The present invention is also directed to novel intermediate compoundsuseful in the preparation of compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, the following terms shall have the followingdefinitions.

“Cycloalkyl” means a non-aromatic, partially or completely saturatedcyclic aliphatic hydrocarbon group containing 3 to 8 atoms. Examples ofcycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl.

“Effective amount” means an amount that is effective to prevent,alleviate or ameliorate symptoms of disease or prolong the survival ofthe subject being treated.

“Halogen” means fluorine, chlorine, bromine or iodine.

“Hetero atom” means an atom selected from N, O and S.

“IC₅₀” refers to the concentration of a particular compound according tothe invention required to inhibit 50% of a specific measured activity.IC₅₀ can be measured, inter alia, as is described in Example 125, infra.

“Lower alkyl” denotes a straight-chain or branched saturated aliphatichydrocarbon having 1 to 6, preferably 1 to 4, carbon atoms. Typicallower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl,t-butyl, 2-butyl, pentyl, hexyl and the like.

“Pharmaceutically acceptable ester” refers to a conventionallyesterified compound of formula I having a carboxyl group, which estersretain the biological effectiveness and properties of the compounds offormula I and are cleaved in vivo (in the organism) to the correspondingactive carboxylic acid. Examples of ester groups which are cleaved (inthis case hydrolyzed) in vivo to the corresponding carboxylic acids(R²⁴C(═O)OH) are lower alkyl esters which may be substituted withNR²⁵R²⁶ where R²⁵ and R²⁶ are lower alkyl, or where NR²⁵R²⁶ takentogether form a monocyclic aliphatic heterocycle, such as pyrrolidine,piperidine, morpholine, N-methylpiperazine, etc.; acyloxyalkyl esters ofthe formula R²⁴C(═O)OCHR²⁷OC(═O)R²⁸ where R²⁷ is hydrogen or methyl, andR²⁸ is lower alkyl or cycloalkyl; carbonate esters of the formulaR²⁴C(═O)OCHR²⁷OC(═O)OR²⁹ where R²⁷ is hydrogen or methyl, and R²⁹ islower alkyl or cycloalkyl; or aminocarbonylmethyl esters of the formulaR²⁴C(═O)OCH₂C(═O)NR²⁵R²⁶ where R²⁵ and R²⁶ are hydrogen or lower alkyl,or where NR²⁵R²⁶ taken together form a monocyclic aliphatic heterocycle,such as pyrrolidine, piperidine, morpholine, N-methylpiperazine, etc.

Examples of lower alkyl esters are the methyl, ethyl, and n-propylesters, and the like. Examples of lower alkyl esters substituted withNR¹⁹R²⁰ are the diethylaminoethyl, 2-(4-morpholinyl)ethyl,2-(4-methylpiperazin-1-yl)ethyl esters, and the like. Examples ofacyloxyalkyl esters are the pivaloxymethyl, 1-acetoxyethyl, andacetoxymethyl esters. Examples of carbonate esters are the1-(ethoxycarbonyloxy)ethyl and 1-(cyclohexyloxycarbonyloxy)ethyl esters.Examples of aminocarbonylmethyl esters are theN,N-dimethylcarbamoylmethyl and carbamoylmethyl esters.

Further information concerning examples of and the use of esters for thedelivery of pharmaceutical compounds is available in Design of Prodrugs.Bundgaard H ed. (Elsevier, 1985). See also, H. Ansel et. al.,Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) atpp. 108-109; Krogsgaard-Larsen, et. al., Textbook of Drug Design andDevelopment (2d Ed. 1996) at pp. 152-191.

“Pharmaceutically acceptable salt” refers to conventional acid-additionsalts or base-addition salts that retain the biological effectivenessand properties of the compounds of formula I and are formed fromsuitable non-toxic organic or inorganic acids or organic or inorganicbases. Sample acid-addition salts include those derived from inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and thosederived from organic acids such as p-toluenesulfonic acid, salicylicacid, methanesulfonic acid, oxalic acid, succinic acid, citric acid,malic acid, lactic acid, fumaric acid, and the like. Samplebase-addition salts include those derived from ammonium, potassium,sodium and, quaternary ammonium hydroxides, such as for example,tetramethylammonium hydroxide. The chemical modification of apharmaceutical compound (i.e. drug) into a salt is a technique wellknown to pharmaceutical chemists to obtain improved physical andchemical stability, hygroscopicity, flowability and solubility ofcompounds. See, e.g., H. Ansel et. al., Pharmaceutical Dosage Forms andDrug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

“Substituted,” as in substituted alkyl, means that the substitution canoccur at one or more positions and, unless otherwise indicated, that thesubstituents at each substitution site are independently selected fromthe specified options.

“Therapeutically effective amount” means an amount of at least onecompound of Formula I, or a pharmaceutically acceptable salt or esterthereof, that significantly inhibits proliferation and/or preventsdifferentiation of a human tumor cell, including human tumor cell lines.

In one embodiment, the invention is directed to a compound of formula

or the pharmaceutically acceptable salts or esters thereof, wherein

R¹ is selected from the group consisting of

H,

lower alkyl that optionally may be substituted from the group selectedfrom OR⁶, cycloalkyl, and NR⁷R⁸,

cycloalkyl,

COR⁹, and

SO₂R¹⁰;

R² is selected from the group consisting of

H,

F,

Cl, and

CH₃;

R³, R⁴ and R⁵ are each independently selected from the group consistingof

H,

lower alkyl, which optionally may be substituted with a group selectedfrom OR⁶ and NR⁷R⁸,

OR¹¹,

NR¹²R¹³,

halogen,

NO₂,

CONR⁶R⁹,

NHSO₂R¹⁴,

CN,

S-lower alkyl,

OCF₃, and

OCHF₂,

or alternatively, R³ and R⁴ taken together with the two carbons and thebond between them from the benzene ring (D) to which R³ and R⁴ areattached can form a ring system having up to two additional rings, eachof said rings having 5-7 atoms, and the ring attached to the benzenering (D) optionally including one or more hetero atoms and beingoptionally substituted by lower alkyl,

provided that R³ and R⁴ are not simultaneously —OCH₃, and providedfurther that R⁴ is not —Cl when R³ is —NO₂;

R⁶ and R⁹ are independently selected from the group consisting of

H, and

lower alkyl that optionally may be substituted by OH and halogen;

R⁷ and R⁸ are independently selected from the group consisting of

H, and

lower alkyl that optionally may be substituted by OR⁶,

or, alternatively, R⁷ is H and R⁸ is OH,

or, alternatively, NR⁷R⁸ can optionally form a ring having 5-6 atoms,said ring optionally including one or more additional hetero atoms andbeing optionally substituted by the group consisting of one or more ofOR⁶ and lower alkyl which itself may be optionally substituted by OH;

R¹⁰ is selected from the group consisting of

lower alkyl which optionally may be substituted by one or more chlorineor fluorine, and

NH₂;

R¹¹ is selected from the group consisting of

H, and

lower alkyl that optionally may be substituted by a group selected fromOR⁶, COOH, halogen and NR¹⁵R¹⁶;

R¹² and R¹³ are independently selected from the group consisting of

H,

lower alkyl that optionally may be substituted with a group selectedfrom OR⁶, COOH and NR¹⁵R¹⁶,

COR¹⁷, and

SO₂R¹⁸,

provided that only one of R¹² and R¹³ is COR¹⁷ or SO₂R¹⁸,

or alternatively NR¹²R¹³ can optionally form a ring having 5-6 atoms,said ring optionally including one or more additional hetero atoms andbeing optionally substituted by the group consisting of one or more ofOR⁶ and lower alkyl which itself may be optionally substituted by OH;

R¹⁴ is lower alkyl;

R¹⁵ and R¹⁶ are independently selected from the group consisting of

H, and

lower alkyl that optionally may be substituted by OH,

or alternatively NR¹⁵R¹⁶ can optionally form a ring having 5-6 atoms,said ring optionally including one or more additional hetero atoms andbeing optionally substituted by the group consisting of one or more ofOR⁶ and lower alkyl which itself may be optionally substituted by OH;

R¹⁷ is selected from the group consisting of

H, and

lower alkyl which optionally may be substituted by OH, COOH and NR¹⁵R¹⁶;and

R¹⁸ is lower alkyl.

In a preferred embodiment of the compounds of formula I, R¹ is selectedfrom the group consisting of H, CH₂CH₂OH, CH₂CH₂CH₂OH, CH₃CO—, CH(CH₃)₂,CH₂CH(CH₃)₂, cyclopropylmethyl and CH₃. More preferably, R¹ is H,methyl, CH₂CH₂CH₂OH, or CH(CH₃)₂.

In another preferred embodiment of the compounds of formula I, R² isselected from the group consisting of H and fluorine, most preferably H.

In another preferred embodiment of the compounds of formula I, R³ isselected from the group OR¹¹, lower alkyl, NH₂, Cl, F, H, , OCHF₂, andNO₂. More preferably, R³ is OCH₃, F, lower alkyl or OCHF₂. Mostpreferably, R³ is F, OCH₃ or CH₂CH₃.

In another preferred embodiment of the compounds of formula I, R⁴ isselected from the group consisting of acetamido, chloro, diethylamino,hydrogen, hydroxy, hydroxyethylamino,[1-(hydroxymethyl)-3-methylbutyl]amino, 1-(3-hydroxymethyl)piperidinyl,4-hydroxy-1-piperidinyl, methoxy, 2-methoxy-ethylamino,2-methyl-1-pyrrolidinyl, morpholino, piperidinyl, pyrrolidinyl. Morepreferably, R⁴ is selected from the group consisting of H and CH₃O—.

When R³ and R⁴ taken together with the benzene ring to which they areattached form a ring system, preferred ring systems are2-dibenzofuranyl, 1,3-benzodioxol-5-yl,2,3-dihydro-1,4-benzodioxin-6-yl, or3,4-dihydro-2H-1,5-benzodioxepin-7-yl, more preferably2,3-dihydro-1,4-benzodioxin-6-yl.

In another preferred embodiment of the compounds of formula I, R⁵ isselected from the group consisting of H, OR¹¹ and F, most preferably H.

In another preferred embodiment of the compounds of formula I,

R¹ is selected from the group consisting of

H, and

lower alkyl that optionally may be substituted by OR⁶;

R² is selected from the group consisting of H and F;

R³ is selected from the group consisting of

H,

lower alkyl

halogen,

NR¹²R¹³

NO₂,

OCHF₂, and

OR¹¹;

R⁴ is selected from the group consisting of

H,

lower alkyl that optionally may be may be substituted by OR⁶,

halogen, and

NR¹²R¹³,

or alternatively, R³ and R⁴ taken together with the two carbons and thebond between them from the benzene ring (D) to which R³ and R⁴ areattached can form a ring system having up to two additional rings, eachof said rings having 5-7 atoms, and the ring attached to the benzenering (D) optionally including one or more hetero atoms and beingoptionally substituted by lower alkyl,

provided that R⁴ is not —Cl when R³ is —NO₂;

R⁶ is selected from the group consisting of

H, and

methyl;

R¹¹ is selected from the group consisting of

H, and

lower alkyl that optionally may be substituted by a group selected fromOR⁶, COOH, halogen and NR¹⁵R¹⁶;

R¹² and R¹³ are independently selected from the group consisting of

H,

lower alkyl that optionally may be substituted with a group selectedfrom OR⁶, COOH and NR¹⁵R¹⁶,

or alternatively NR¹²R¹³ can optionally form a ring having 5-6 atoms,said ring optionally including one or more additional hetero atoms andbeing optionally substituted by the group consisting of one or more ofOR⁶ and lower alkyl which itself may be optionally substituted by OH;and

R¹⁵ and R¹⁶ are independently selected from the group consisting of

H, and

lower alkyl that optionally may be substituted by OH,

or alternatively NR¹⁵R¹⁶ can optionally form a ring having 5-6 atoms,said ring optionally including one or more additional hetero atoms andbeing optionally substituted by the group consisting of one or more ofOR⁶ and lower alkyl which itself may be optionally substituted by OH.

In a most preferred embodiment of the compounds of formula I,

R¹ is selected from the group consisting of

H,

CH₂CH₂OH,

CH₂CH₂CH₂OH,

CH₃CO—,

CH(CH₃)₂,

CH₂CH(CH₃)₂,

cyclopropylmethyl, and

CH₃;

R² is selected from the group consisting of

H and F;

R³ is selected from the group consisting of

OR¹¹,

lower alkyl,

NH₂,

Cl,

F,

H,

OCHF₂, and

NO₂;

R⁴ is selected from the group consisting of

H, and

diethylamino;

R⁵ is H; and

R¹¹ is unsubstituted lower alkyl.

In another most preferred embodiment of the compounds of formula I,

R¹ is selected from the group consisting of

H,

CH₂CH₂CH₂OH,

CH(CH₃)₂,

CH₃, and

cyclopropylmethyl;

R², R⁴ and R⁵ are H; and

R³ is selected from the group consisting of

OCH₃,

F, and

CH₂CH₃.

The following are examples of preferred compounds of formula I:

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](2,3-dihydro-1,4-benzodioxin-6-yl)methanone(Example 24),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](1,3-benzodioxol-5-yl)methanone(Example 25),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(1-pyrrolidinyl)phenyl]methanone(Example 26),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(1-piperidinyl)phenyl]methanone(Example 27),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(4-morpholinyl)phenyl]methanone,acetate salt (Example 28),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3,4-dihydro-2H-1,5-benzodioxepin-7-yl)methanone(Example 29),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl]-(4-hydroxyphenyl)methanone(Example 30),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3-nitrophenyl)methanone(Example 31),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](4-methoxyphenyl)methanone(Example 32),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(diethylamino)phenyl]methanone(Example 33),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](2-dibenzofuranyl)methanone(Example 34),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3-fluoro-4-methoxyphenyl)methanone(Example 35),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3-methoxyphenyl)methanone(Example 36),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3,4-dichlorophenyl)methanone(Example 37),

[4-Amino-2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](1,3-benzodioxol-5-yl)methanone(Example 38),

[4-Amino-2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3,5-dimethoxyphenyl)methanone(Example 39),

[4-Amino-2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3-methoxyphenyl)methanone(Example 40),

[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](2,3-dihydro-1,4-benzodioxin-6-yl)methanone(Example 41),

[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](1,3-benzodioxol-5-yl)methanone(Example 42),

[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](3-methoxyphenyl)methanone(Example 43),

[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](3,5-dimethoxyphenyl)methanone(Example 44),

N-[4-[[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl]carbonyl]phenyl]acetamide(Example 45),

[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl][4-(diethylamino)phenyl]methanone(Example 46),

1-Acetyl-4-[4-[[4-amino-5-[(1,3-benzodioxol-5-yl)carbonyl]-2-thiazolyl]amino]phenyl]piperazine(Example 47),

1-Acetyl-4-[4-[[4-amino-5-[4-(diethylamino)benzoyl]-2-thiazolyl]amino]phenyl]piperazine,trifluoroacetate salt (Example 48),

[4-Amino-2-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-5-thyiazolyl](2,3-dihydro-1,4-benzodioxin-6-yl)methanone(Example 49),

[4-Amino-2-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl][4-(1-pyrrolidinyl)phenyl]methanone(Example 50),

[4-Amino-2-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](3-fluorophenyl)methanone(Example 51),

[4-Amino-2-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](3,5-difluorophenyl)methanone(Example 52),

[4-Amino-2-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](3-methoxyphenyl)methanone(Example 53),

[4-Amino-2-[[4-(1-piperazinyl)phenyl]amino]-5-thiazolyl](3-fluorophenyl)methanone(Example 54),

[4-Amino-2-[[4-(1-piperazinyl)phenyl]amino)-5-thiazolyl][4-(1-pyrrolidinyl)phenyl]methanone(Example 55),

[4-Amino-2-[[4-(1-piperazinyl)phenyl]amino)-5-thiazolyl](3-fluoro-4-methoxyphenyl)methanone(Example 56),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(2-hydroxyethyl)amino-3-nitrophenyl]methanone(Example 57),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-(1-pyrrolidinyl)phenyl]methanone(Example 58),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl)[3-nitro-4-(4-morpholinyl)phenyl]methanone(Example 59),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-[(2-methoxyethyl)amino]phenyl]methanone(Example 60),

racemic[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-[3-(hydroxymethyl)-1-piperidinyl]phenyl]methanone(Example 61),

racemic[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-(2-methyl-1-pyrrolidinyl)phenyl]methanone(Example 62),

(R)-[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-[[1-(hydroxymethyl)-3-methylbutyl]amino]phenyl]methanone(Example 63),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-(4-hydroxy-1-piperidinyl)phenyl]methanone(Example 64),

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-amino-4-(4-pyrrolidinyl)phenyl]methanone(Example 65),

(R)-[3-Amino-4-[[1-(hydroxymethyl)-3-methylbutyl]amino]phenyl][4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl]methanone(Example 66),

[4-Amino-2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](2,3-dihydro-1,4-benzodioxin-5-yl)methanone (Example 67),

[4-Amino-2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(1-pyrrolidinyl)phenyl]methanone (Example 68),

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-methoxy-phenyl)-methanone,phosphoric acid (Example 69),

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}(3methylsulfanyl-phenyl)-methanone(Example 70).

(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-fluoro-phenyl)-methanone(Example 71),

(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-methoxy-phenyl)-methanone(Example 72),

3-(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazole-5-carbonyl)-benzonitrile(Example 73),

(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-nitro-phenyl)-methanone(Example 74),

(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-m-tolyl-methanone(Example 75),

(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-ethyl-phenyl)-methanone(Example 76),

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-ethyl-phenyl)-methanone(Example 77),

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-m-tolyl-methanone(Example 78),

3-{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazole-5-carbonyl}-benzonitrile(Example 79).

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-phenyl)-methanone,with hydrogen bromide (Example 80),

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3,4,5-trifluoro-phenyl)-methanone,with hydrogen bromide (Example 81),

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3,5-difluoro-phenyl)-methanone,with hydrogen bromide (Example 82),

4-Amino-2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-fluoro-4-methoxy-phenyl)-methanone,hydrogen bromide (Example 83),

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(4-fluoro-3-methoxy-phenyl)-methanone,with hydrogen bromide (Example 84),

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-4-methoxy-phenyl)-methanone,with hydrogen bromide (Example 85),

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(4-difluoromethoxy-phenyl)-methanone,with hydrogen bromide (Example 86),

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-trifluoromethoxy-phenyl)-methanone,with hydrogen bromide (Example 87),

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(4-piperidin-1-yl-phenyl)-methanone,with hydrogen bromide (Example 88),

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(4-morpholin-4-yl-phenyl)-methanone,with hydrogen bromide (Example 89),

(4-Amino-2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3,5-difluoro-phenyl)-methanone,with hydrogen bromide (Example 90),

(4-Amino-2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3,4-difluoro-phenyl)-methanone,with hydrogen bromide (Example 91),

(4-Amino-2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-methoxy-phenyl)-methanone,with hydrogen bromide (Example 92),

(4-Amino-2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-benzo[1,3]dioxol-5-yl-methanone,with hydrogen bromide (Example 93),

4-Amino-2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone,with hydrogen bromide (Example 94),

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3,5-difluoro-phenyl)-methanone,with hydrogen bromide (Example 95),

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3,5-difluoro-4-methoxy-phenyl)-methanone,with hydrogen bromide (Example 96),

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(4-fluoro-3-methoxy-phenyl)-methanone,with hydrogen bromide(Example 97),

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-trifluoromethoxy-phenyl)-methanone,with hydrogen bromide (Example 98),

(4-Amino-2-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-fluoro-phenyl)-methanone,with acetic acid (Example 99),

[4-Amino-2-(4-piperazin-1-yl-phenylamino)-thiazol-5-yl]-(3,4,5-trifluoro-phenyl)-methanone,with acetic acid (Example 100),

[4-Amino-2-(4-piperazin-1-yl-phenylamino)-thiazol-5-yl]-(3,5-difluoro-4-methoxy-phenyl)-methanone,with acetic acid (Example 101),

[4-Amino-2-(4-piperazin-1-yl-phenylamino)-thiazol-5-yl]-(4-fluoro-3-methoxy-phenyl)-methanone,with acetic acid (Example 102),

[4-Amino-2-(4-piperazin-1-yl-phenylamino)-thiazol-5-yl]-(3-trifluoromethoxy-phenyl)-methanone,with acetic acid (Example 103),

{4-Amino-2-[4-(4-sec-butyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-phenyl)-methanone(Example 104),

{4-Amino-2-[4-(4-sec-butyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-benzo[1,3]dioxol-5-yl-methanone(Example 105),

{4-Amino-2-[4-(4-sec-butyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone(Example 106),

{4-Amino-2-[4-(4-cyclopentyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-benzo[1,3]dioxol-5-yl-methanone(Example 107),

{4-Amino-2-[4-(4-cyclopentyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone(Example 108),

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-trifluoromethoxy-phenyl)-methanone(Example 109),

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-phenyl)-methanone(Example 110),

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino)-thiazol-5-yl}-(3-difluoromethoxy-phenyl)-methanone(Example 111),

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-hydroxy-phenyl)-methanone,with acetic acid (Example 112),

{4-Amino-2-[4-(4-isobutyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-hydroxy-phenyl)-methanone,with acetic acid (Example 113),

[4-Amino-2-(4-piperazin-1-yl-phenylamino)-thiazol-5-yl]-(3-difluoromethoxy-phenyl)-methanone(Example 114),

{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-difluoromethoxy-phenyl)-methanone(Example 115),

{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-methoxy-phenyl)-methanone(Example 116),

{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-benzo[1,3]dioxol-5-yl-methanone(Example 117),

{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone(Example 118),

{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-4-hydroxy-phenyl)-methanone(Example 119),

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-difluoromethoxy-phenyl)-methanone(Example 120),

{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-phenyl)-methanone(Example 121),

{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-4-methoxy-phenyl)-methanone(Example 122),

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-hydroxy-phenyl)-methanone(Example 123), and

3-{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazole-5-carbonyl}-benzonitrile(Example 124).

The compounds disclosed herein and covered by formula I above mayexhibit tautomerism or structural isomerism. It is intended that theinvention encompasses any tautomeric or structural isomeric form ofthese compounds, or mixtures of such forms, and is not limited to anyone tautomeric or structural isomeric form depicted in the formulaabove.

General Synthesis of Compounds According to the Invention

The compounds of the present invention can be prepared by anyconventional means. Suitable processes for synthesizing these compoundsare provided in the examples. Generally, compounds of formula I can beprepared according to one of the below described synthetic routes.

A. Ring Formation

Compounds of the invention can be prepared by the alkylation andcyclization of a number of thiourea derivatives, as shown in Scheme I,using reactions that are known. Among the thiourea derivatives that canbe used are nitroamidinothioureas (Binu, R. et al. Org. Prep. Proced.Int. 1998, 30, 93-96);1-[(arylthiocarbamoyl)amino]-3,5-dimethylpyrazoles (Jenardanan, G. C. etal. Synth. Commun. 1997, 27, 3457-3462); andN-(aminoiminomethyl)-N′-phenylthioureas (Rajasekharan, K. N. et al.Synthesis 1986, 353-355).

Another thiourea derivative that can be used for the preparation ofcompounds of the invention by alkylation and cyclization isN-cyanothiourea (Gewald, K. et al. J. Prakt. Chem. 1967, 97-104). Forexample, pursuant to Scheme IA below, an N-cyanothiourea of formula 4Acan be reacted with a halomethylketone, such as a bromomethylketone offormula 5, at a temperature between around room temperature and around65° C., to give a compound of formula 6.

Alternatively, the compounds of the invention are also convenientlyprepared by reaction of a resin-bound substituted (aminothioxomethyl)carbamimidothioic acid methyl ester of formula 8 with a bromomethyl arylketone of formula 5 as shown in Scheme II below.

The resin-bound thiourea derivative of formula 8 can be made by anyconventional procedure known to one skilled in the art of organicsynthesis. For example, it can be conveniently prepared by the reactionof a resin-bound thiouronium salt of formula 7 with an isothiocyanate offormula 2 in the presence of a base, such as a tertiary amine (e.g.,triethylamine or diisopropylethylamine) in an inert solvent, such as apolar aprotic solvent (e.g., N,N-dimethylformamide). The reaction isconveniently carried out at a temperature around room temperature. Theresin-bound thiourea derivative of formula 8 is then converted to theproduct of formula 6 by treatment with a halomethylketone (for example,a bromomethylketone of formula 5) in a suitable inert solvent such as apolar aprotic solvent (e.g., N,N-dimethylformamide) at a temperaturearound room temperature.

B. Nucleophilic Aromatic Substitution

As shown in Scheme III above, compounds of formula 1 where R³ representsnitro, R⁴ represents NR²⁰R²¹ (wherein R²⁰ and R²¹ are independentlyselected from H and lower alkyl which itself can be substituted by OH,or alternatively, NR²⁰R²¹ can optionally form a ring having 5-6 atoms,said ring including one or more additional hetero atoms and beingoptionally substituted by OH and lower alkyl which itself may besubstituted by OH) and R⁵ represents hydrogen (that is to say, compoundsof formula 10), can be conveniently prepared by treating a compound offormula 9 , with an amine of formula HNR²¹R²⁰, in the optional presenceof an additional base, such as a tertiary amine (e.g., triethylamine ordiisopropylethylamine) in an inert solvent, such as a lower alcohol(e.g., ethanol, isopropanol, n-butanol, or the like) or a polar aproticsolvent (e.g., N,N-dimethylformamide). The reaction is convenientlycarried out a temperature between about 70 degrees and about 110degrees, preferably at about the reflux temperature of the solvent orabout 100 degrees, whichever is lower.

C. Removal of Protective Groups

As shown in Scheme IV, compounds of formula I where R¹ represents H(that is, compounds of formula 11) can be prepared by removal of aprotective group from compounds of formula 30 where R³⁰ represents aprotective group commonly used for the protection of a secondary amine.Many such protective groups are known to those of skill in the art oforganic synthesis. For example, several suitable protective groups areenumerated in “Protective Groups in Organic Synthesis” (Greene, T. W.and Wuts, P. G. M., 2^(nd) Edition, John Wiley & Sons, N.Y. 1991).Preferred protective groups are those compatible with the reactionconditions used to prepare compounds of the invention. One suchprotective group is the tert-butoxycarbonyl (t-BOC) group. Thetert-butoxy carbonyl group can be conveniently removed by treatment of acompound of formula 30 in which R³⁰ represents

with an acid to give a compound of formula I in which R¹ represents H.Examples of acids that can be used to effect this transformation arewell known, and include trifluoroacetic acid, hydrochloric acid,hydrofluoric acid, and aluminum chloride. For example, the t-BOC groupmay be conveniently removed by treating a compound of formula 30 inwhich R³⁰ represents

with trifluoroacetic acid, in an inert solvent, such as a halogenatedhydrocarbon (e.g., dichloromethane). The reaction can be carried out ata temperature between about 0 degrees and about room temperature,preferably at about room temperature.

D. Separating a Mixture of Stereoisomers into the Optically PureStereoisomers (When Compound of Formula I is Chiral)

The optional separation of isomeric structures of formula I can becarried out according to known methods such as for example resolution orchiral high pressure liquid chromatography (also known as chiral HPLC).Resolution methods are well known, and are summarized in “Enantiomers,Racemates, and Resolutions” (Jacques, J. et al. John Wiley and Sons, NY,1981). Methods for chiral HPLC are also well known, and are summarizedin “Separation of Enantiomers by Liquid Chromatographic Methods”(Pirkle, W. H. and Finn, J. in “Asymmetric Synthesis”, Vol. 1, Morrison,J. D., Ed., Academic Press, Inc., NY 1983, pp. 87-124).

E. Converting a Compound of Formula I that Bears a Basic Nitrogen into aPharmaceutically Acceptable Acid Addition Salt

The optional conversion of a compound of formula I that bears a basicnitrogen into a pharmaceutically acceptable acid addition salt can beeffected by conventional means. For example, the compound can be treatedwith an inorganic acid such as for example hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or withan appropriate organic acid such as acetic acid, citric acid, tartaricacid, methanesulfonic acid, p-toluenesulfonic acid, or the like.

F. Converting a Compound of Formula I that Bears a Carboxylic Acid Groupinto a Pharmaceutically Acceptable Alkali Metal Salt

The optional conversion of a compound of formula I that bears acarboxylic acid group into a pharmaceutically acceptable alkali metalsalt can be effected by conventional means. For example, the compoundcan be treated with an inorganic base such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, or the like.

G. Converting a Compound of Formula I that Bears a Carboxylic Acid Groupinto a Pharmaceutically Acceptable Ester

The optional conversion of a compound of formula I that bears acarboxylic acid group into a pharmaceutically acceptable ester can beeffected by conventional means. The conditions for the formation of theester will depend on the stability of the other functional groups in themolecule to the reaction conditions. If the other moieties in themolecule are stable to acidic conditions, the ester may be convenientlyprepared by heating in a solution of a mineral acid (e.g., sulfuricacid) in an alcohol. Other methods of preparing the ester, which may beconvenient if the molecule is not stable to acidic conditions includetreating the compound with an alcohol in the presence of a couplingagent and in the optional presence of additional agents that mayaccelerate the reaction. Many such coupling agents are known to oneskilled in the art of organic chemistry. Two examples aredicyclohexylcarbodiimide and triphenylphosphine/diethylazodicarboxylate. In the case where dicyclohexylcarbodiimide is used asthe coupling agent, the reaction is conveniently carried out by treatingthe acid with the alcohol, dicyclohexylcarbodiimide, and the optionalpresence of a catalytic amount (0-10 mole %) ofN,N-dimethylaminopyridine, in an inert solvent such as a halogenatedhydrocarbon (e.g., dichloromethane) at a temperature between about 0degrees and about room temperature, preferably at about roomtemperature. In the case where triphenylphosphine/diethylazodicarboxylate is used as the coupling agent, the reaction isconveniently carried out by treating the acid with the alcohol,triphenylphosphine and diethyl azodicarboxylate, in an inert solventsuch as an ether (e.g., tetrahydrofuran) or an aromatic hydrocarbon(e.g., benzene) at a temperature between about 0 degrees and about roomtemperature, preferably at about 0 degrees.

Turning to the intermediates, isothiocyanate intermediates of formula 2used to make compounds of the invention can be made by any conventionalmeans. For example, they may be made by the route shown in Scheme Vbelow.

The nitro group in a compound of formula 12 can be reduced to give ananiline of formula 13 using a number of methods familiar to one skilledin the art. These methods include (1) treatment of the nitro compound offormula 12 with iron/acetic acid, with tin(II) chloride/hydrochloricacid, or with zinc and ammonium chloride; and (2) hydrogenation in thepresence of a noble metal catalyst such as palladium-on-carbon.

The isothiocyanates of formula 2 may be made from anilines of formula 13using any one of a number of reagents known to those skilled in organicsynthesis to be useful for the transformation of an aniline of formula13 into an isothiocyanate of formula 2. Among these reagents are carbondisulfide, thiophosgene, 1,1′-thiocarbonylbis(2-pyridone), andthiocarbonyl diimidazole. The reaction can be carried out by treating ananiline of formula 13 with thiocarbonyl diimidazole in a suitable inertsolvent such as a polar aprotic solvent (e.g., N,N-dimethylformamide) ata temperature between about −20 degrees and about 0 degrees, preferablyat about −15 degrees.

Nitro compounds of formula 12 can be made by a variety of methods thatare known in the field of organic synthesis. For example, they may bemade by the nucleophilic substitution of a nitrobenzene derivative thatbears a leaving group at the position para to the nitro group inaccordance with Scheme VI below:

The nucleophilic substitution reaction between an amine of formula 15and a nitrobenzene of formula 14 (wherein X is a leaving group) to givethe substituted product of formula 12 can be conveniently carried out byheating these materials together at a temperature between about 50 andabout 100 degrees, preferably at about 80 degrees, in the optionalpresence of an inert solvent such as acetonitrile (Scheme VI). Suitableleaving groups of formula X include chloride and fluoride. By way ofexample and not as a limitation, the following compounds of formula 14are available commercially from the noted vendors:

Supplier

Aldrich

Aldrich

Aldrich

Lancaster Synthesis

Aldrich

Alternatively, nitro compounds of formula 12 may be synthesizedaccording to Scheme VII below.

The alkylation of compounds of formula 16 to give compounds of formula12, in which R¹ represents an alkyl group can be achieved by treatingthe compound with an alkylating agent of formula 17, in which Xrepresents one of a number of leaving groups well known to those withknowledge of organic synthesis, such as a halide (e.g., chloride,bromide, iodide) or a sulfonate (e.g., mesylate, tosylate, triflate), orthe like, in an inert solvent, such as acetonitrile, a lower alkylketone (e.g., acetone or 2-butanone), a polar aprotic solvent (e.g.,N,N-dimethylformamide), or an aromatic hydrocarbon (e.g., benzene ortoluene), in the presence of a base, such as sodium carbonate orpotassium carbonate, and in the optional presence of a catalyst such aspotassium iodide. Except where the leaving group is triflate, thereaction can be conveniently carried out at a temperature between about50 degrees and about 110 degrees, preferably at about 80 degrees. Wherethe leaving group is triflate, the reaction is conveniently carried outat a temperature between about 0 degrees and room temperature,preferably at about room temperature.

Compounds of formula 12 where R¹ represents an acyl group may beprepared by acylation of compounds of formula 16. The reaction can beeffected using known methods. For example, the compound of formula 16can be treated with a carboxylic acid of formula 17, in which Xrepresents OH, in the presence of a coupling agent, many examples ofwhich are well known per se in peptide chemistry, and in the optionalpresence of a substance that increases the rate of the reaction, such as1-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole; or by reactionof the compound of formula 16 with a reactive derivative of carboxylicacids such as the corresponding acid halides (for example, the acidchloride), acid anhydride, mixed anhydride, activated ester, etc. Thereaction is conveniently carried out by treating the compound of formula16 with an acid chloride in the presence of a base such as pyridine, ora tertiary amine (e.g., diisopropylethylamine) or an inorganic base suchas sodium or potassium carbonate, in an inert solvent such as ahalogenated hydrocarbon (e.g., dichloromethane) at a temperature betweenabout 0 degrees and about room temperature, preferably at about roomtemperature.

Compounds of formula 12 where R¹ represents an alkoxycarbonyl group maybe prepared by the alkoxycarbonylation of compounds of formula 16 togive compounds of formula 12, in which R¹ represents an alkoxycarbonylgroup. This synthesis can be effected using reactions that are wellknown in the fields of organic chemistry and peptide chemistry.Conditions for many of these reactions are given in “Protective Groupsin Organic Synthesis” (Greene, T. W. and Wuts, P. G. M., 2^(nd) Edition,John Wiley & Sons, N.Y. 1991). In the case of the preferredalkoxycarbonyl protective group, namely the tert-butoxycarbonyl (t-BOC)group, the protective group can be introduced by reacting the amine offormula 16 with di-tert-butyl dicarbonate in an inert solvent such as amixture of water and an ether such as dioxane, or in a halogenatedsolvent (such as dichloromethane), or in acetonitrile, in the optionalpresence of a base or of a catalyst, such as N,N-dimethylamino-pyridine.As an alternative to di-tert-butyl dicarbonate, the following reagentscould also be used: 2-(tert-butoxycarbonyloximino)-2-phenylacetonitrile,or tert-butyl azidoformate.

Compounds of formula 12 where R¹ represents a sulfonyl group may beprepared by the sulfonylation of compounds of formula 16 to givecompounds of formula 12, in which R¹ represents a sulfonyl group. Thissynthesis can be effected using reactions that are well known in thefield of organic chemistry. For example, compounds of formula 12 inwhich R¹ represents a sulfonyl group can be prepared by reaction ofcompounds of formula 16 with a sulfonyl chloride in the presence of anappropriate base for example pyridine that can also be used as solvent.The reaction may also be performed by using a tertiary amine as thebase, in the presence of an inert solvent such as tetrahydrofuran ordichloro-methane; or in aqueous solution using an alkali metal hydroxidesuch as sodium hydroxide as the base. The reaction is convenientlycarried out at a temperature of between about room temperature and about80 degrees, preferably at about room temperature.

Sample compounds of formula 16 may be obtained as indicated below.

Available commercially (Aldrich)

Can be prepared by the procedure of Brickner, S. J. et al. J. Med. Chem.1996, 39, 673-679

Can be prepared by the procedure of Kemp, J. E. G. et al. EP 257864

Can be prepared from 2-chloro-5-nitrotoluene (Aldrich) by proceduresanalogous to those described in Kemp, J. E. G. et al. EP 257864 for thepreparation of 1-(2-chloro-4-nitrophenyl)piperazine

Bromomethylketone intermediates 5 used to make compounds of theinvention are available commercially or can be made using one of anumber of methods known to those skilled in the art of organicsynthesis, for example: Friedel-Crafts reactions of an arene withbromoacetyl bromide or bromoacetyl chloride; oxidation of a2-bromo-1-phenethyl alcohol; reaction of a diazomethyl ketone with HBr;reduction of a dibromomethyl ketone (see Scheme VIII) below; or reactionof a methyl ketone with a brominating agent (see Scheme IX) such asbromine, copper(II) bromide, tetrabutylammonium tribromide, or5,5-dibromo-barbituric acid.

According to the method of Diwu et al. (Tetrahedron Lett. 1998, 39,4987-4990), methyl ketones of formula 19 can be converted into thecorresponding dibromomethyl ketones of formula 20 by treatment withbromine in neat sulfuric acid. The dibromomethyl ketones of formula 20can then be converted into the desired bromomethyl ketones of formula 5by reduction with diethylphosphite.

Bromomethyl ketones of formula 5 can also be prepared directly frommethyl ketones of formula 19 using a variety of reagents well known tothose of ordinary skill in the art of organic synthesis, such as thosementioned above. For example, the reaction may be conveniently carriedout by treating the methyl ketone of formula 19 with bromine in asuitable inert solvent such as a halogenated hydrocarbon (e.g., carbontetrachloride) in the optional presence of other agents that facilitatethe reaction, such as a Bronsted or Lewis acid catalyst (e.g., aluminumchloride or acetic acid). The optimal reaction temperature depends onwhether or not a catalyst is used. In the case where aluminum chlorideis used, the reaction is conveniently carried out at about 0 degrees. Inthe cases where acetic acid is added, or where no catalyst is used, thereaction is conveniently carried out at a temperature between about roomtemperature and about 80 degrees, preferably at about room temperature.Alternatively, a methyl ketone of formula 19 may be converted to abromomethylketone of formula 5 by treatment with copper(II) bromide in asuitable unreactive solvent such as ethyl acetate, preferably at thereflux temperature.

Compositions/Formulations

In an alternative embodiment, the present invention is directed topharmaceutical compositions comprising at least one compound of formulaI, or a pharmaceutically acceptable salt or ester thereof.

These pharmaceutical compositions can be administered orally, forexample in the form of tablets, coated tablets, dragees, hard or softgelatin capsules, solutions, emulsions or suspensions. They can also beadministered rectally, for example, in the form of suppositories, orparenterally, for example, in the form of injection solutions.

The pharmaceutical compositions of the present invention comprisingcompounds of formula I, and/or the salts or esters thereof, may bemanufactured in a manner that is known in the art, e.g. by means ofconventional mixing, encapsulating, dissolving, granulating,emulsifying, entrapping, dragee-making, or lyophilizing processes. Thesepharmaceutical preparations can be formulated with therapeuticallyinert, inorganic or organic carriers. Lactose, corn starch orderivatives thereof, talc, steric acid or its salts can be used as suchcarriers for tablets, coated tablets, dragees and hard gelatin capsules.Suitable carriers for soft gelatin capsules include vegetable oils,waxes and fats. Depending on the nature of the active substance, nocarriers are generally required in the case of soft gelatin capsules.Suitable carriers for the manufacture of solutions and syrups are water,polyols, saccharose, invert sugar and glucose. Suitable carriers forinjection are water, alcohols, polyols, glycerine, vegetable oils,phospholipids and surfactants. Suitable carriers for suppositories arenatural or hardened oils, waxes, fats and semi-liquid polyols.

The pharmaceutical preparations can also contain preserving agents,solubilizing agents, stabilizing agents, wetting agents, emulsifyingagents, sweetening agents, coloring agents, flavoring agents, salts forvarying the osmotic pressure, buffers, coating agents or antioxidants.They can also contain other therapeutically valuable substances,including additional active ingredients other than those of formula I.

Dosages

As mentioned above, the compounds of the present invention, includingthe compounds of formula I, are useful in the treatment or control ofcell proliferative disorders, in particular oncological disorders. Thesecompounds and formulations containing said compounds are particularlyuseful in the treatment or control of solid tumors, such as, forexample, breast, colon, lung and prostate tumors.

A therapeutically effective amount of a compound in accordance with thisinvention means an amount of compound that is effective to prevent,alleviate or ameliorate symptoms of disease or prolong the survival ofthe subject being treated. Determination of a therapeutically effectiveamount is within the skill in the art.

The therapeutically effective amount or dosage of a compound accordingto this invention can vary within wide limits and may be determined in amanner known in the art. Such dosage will be adjusted to the individualrequirements in each particular case including the specific compound(s)being administered, the route of administration, the condition beingtreated, as well as the patient being treated. In general, in the caseof oral or parenteral administration to adult humans weighingapproximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg,preferably from about 200 mg to about 1,000 mg, should be appropriate,although the upper limit may be exceeded when indicated. The dailydosage can be administered as a single dose or in divided doses, or forparenteral administration, it may be given as continuous infusion.

Starting Materials

In another embodiment, the present invention is also directed to novelintermediates useful in the preparation of compounds of formula I. Thesenovel intermediates include the following compounds:

1-(2-Fluoro-4-isothiocyanatophenyl)-4-methylpiperazine (Example 2C),

1-(1-Methylethyl)-4-(4-nitrophenylpiperazine) (Example 3A),

4-[4-(1-Methylethyl)-1-piperazinyl]benzenamine (Example 3B),

1-(4-Isothiocyanatophenyl)-4-(1-methylethyl)piperazine (Example 3C),

4-(2-Hydroxyethyl)-1-(4-isothiocyanatophenyl)piperazine (Example 5B),

1-(4-Isothiocyanatophenyl)-4-(2-methoxy-ethyl)piperazine (Example 14B),

1-(4-Isothiocyanatophenyl)-4-(1-methylpropyl)piperazine (Example 14C),

4-Cyclopentyl-1-(4-isothiocyanatophenyl)piperazine (Example 14D),

1-(4-Isothiocyanatophenyl)-4-(2-methylpropyl)piperazine (Example 14E),

4-(3-Hydroxypropyl)-1-(4-isothiocyanatophenyl)piperazine (Example 14F),

2-Bromo-1-(3,4,5-trifluoro-phenyl)ethanone (Example 14H),

2-Bromo-1-(4-fluoro-3-methoxy-phenyl)ethanone (Example 14I),

2-Bromo-1-(4-fluoro-3-methoxy-phenyl)ethanone (Example 14K),

2-Bromo-1-(3-difluoromethoxy-phenyl)ethanone (Example 14L),

[4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](4-chloro-3-nitrophenyl)methanone(Example 15),

Carbamimidothioic acid,[[4-(4-methyl-1-piperazinyl)phenylamino]thioxomethyl], polymer bound(Example 18),

Carbamimidothioic acid,[[3-fluoro-4-(4-methyl-1-piperazinyl)phenylamino]thioxomethyl], polymerbound (Example 19),

Carbamimidothioic acid,[[4-[4-(1-methylethyl)-1-piperazinyl]phenylamino]thioxomethyl], polymerbound (Example 20),

Carbamimidothioic acid,[[4-(4-acetyl-1-piperazinyl)phenylamino]thioxomethyl], polymer bound(Example 21),

Carbamimidothioic acid,[[4-[4-(2-hydroxyethyl)-1-piperazinyl]phenylamino]thioxomethyl], polymerbound (Example 22),

Carbamimidothioic acid,[[4-[4-[(1,1-dimethylethoxy)carbonyl]-1-piperazinyl]phenylamino]thioxomethyl],polymer bound (Example 23A),

Carbamimidothioic acid,[[4-[4-(2-methoxyethyl)-1-piperazinyl]phenylamino]thioxomethyl], polymerbound (Example 23B),

Carbamimidothioic acid,[[4-[4-(1-methylpropyl)-1-piperazinyl]phenylamino]thioxomethyl], polymerbound (Example 23C),

Carbamimidothioic acid,[[4-(4-cyclopentyl-1-piperazinyl)phenylamino]thioxomethyl], polymerbound (Example 23D),

Carbamimidothioic acid,[[4-[4-(2-methylpropyl)-1-piperazinyl]phenylamino]thioxomethyl], polymerbound (Example 23E),

Carbamimidothioic acid,[[4-[4-(3-hydroxypropyl)-1-piperazinyl]phenylamino]thioxomethyl],polymer bound (Example 23F),

4-[4-[[4-Amino-5-(3-fluorobenzoyl)-2-thiazolyi]amino]phenyl]-1-piperazinecarboxylicacid, 1,1-dimethylethyl ester (Example 54A),

4-[4-[[4-Amino-5-[4-(1-pyrrolidinyl)benzoyl]-2-thiazolyl]amino]phenyl]-1-piperazinecarboxylicacid, 1,1-dimethylethyl ester (Example 55A),

4-[4-[[4-Amino-5-(3-fluoro-4-methoxybenzoyl)-2-thiazolyl]amino]phenyl]-1-piperazinecarboxylicacid, 1,1-dimethylethyl ester (Example 56A).

EXAMPLES

The following examples illustrate preferred methods for synthesizing thecompounds and formulations of the present invention.

Example 1

1-(4-Isothiocyanatophenyl)-4-methylpiperazine

A mixture of thiocarbonyidiimidazole (4.46 g, 25.0 mmol) (Aldrich) andN,N-dimethylformamide (20 mL) was cooled to about −15° C. and a solutionof 4-(4-methyl-1-piperazinyl)benzenamine (prepared according to theprocedure of Chong, W. K. et al. WO9921845; 4.78 g, 25.0 mmol) was addedover a period of 30 min. The cooling bath was removed and the mixturewas stirred for 1 h. The mixture was cooled to 0° C. and ice-water wasadded. After 30 min, the mixture was extracted with ether (3×200 mL),dried (Na₂SO₄), filtered, and evaporated to give1-(4-isothiocyanatophenyl)-4-methylpiperazine (4.84 g, 83%) as a palepurple solid.

Example 2

1-(2-Fluoro-4-isothiocyanatophenyl)-4-methylpiperazine

A. 1-(2-Fluoro-4-nitrophenyl)-4-methylpiperazine

A solution of 3,4-difluoronitrobenzene (12.00 g, 75.4 mmol) (Aldrich)and N-methylpiperazine (18.89 g, 188.6 mmol) in acetonitrile (150 mL)was heated at reflux for 3 h. The reaction mixture was allowed to standovernight at room temperature, then the solvent was evaporated underreduced pressure and the residue was partitioned between water and ethylacetate (200 mL each). The aqueous layer was extracted with ethylacetate (3×200 mL) and the combined organic layers were then washed withwater and brine (200 mL each), dried (MgSO4), filtered, and evaporatedunder reduced pressure to give1-(2-fluoro-4-nitrophenyl)-4-methylpiperazine as a pale brown solid(17.5 g, 97%, mp 68-70° C.).

B. 3-Fluoro-4-(4-methyl-1-piperazinyl)benzenamine

A solution of 1-(2-fluoro-4-nitrophenyl)-4-methylpiperazine (5.00 g,20.9 mmol) (from Step A above) and 10% palladium-on-carbon (0.20 g, 0.2mmol) in ethyl acetate (100 mL) and ethanol (50 mL) was hydrogenated at50 psi in a Parr shaker for 4 h. The mixture was filtered throughCelite™. The Celite™ was washed with ethyl acetate (50 mL) and thesolvent was evaporated to give3-fluoro-4-(4-methyl-1-piperazinyl)benzenamine as a white solid (4.05 g,93%, mp 89-91° C.).

C. 1-(2-Fluoro-4-isothiocyanatophenyl)-4-methylpiperazine

Thiocarbonyl diimidazole (3.00 g, 3.53 mmol) (Aldrich) was dissolved inN,N-dimethylformamide (10 mL) and the solution was cooled to −10° C.(ice/acetone bath). A solution of 3-fluoro-4-(4-methyl-1-piperazinyl)benzenamine (2.26 g, 10.8 mmol) (from Step B above) inN,N-dimethylformamide (30 mL) was added over a period of 30 minutes,then the cooling bath was removed and the solution was stirredovernight. Ice-water was then added (100 mL) and the mixture wasextracted with ether (3×200 mL). The combined ether layers were dried(MgSO4), filtered, and evaporated to give1-(2-fluoro-4-isothio-cyanatophenyl)-4-methylpiperazine as a yellow oilthat solidified on standing (3.88 g, 92%).

Example 3

1-(4-Isothiocyanatophenyl)-4-(1-methylethyl)piperazine

A. 1-(1-Methylethyl)-4-(4-nitrophenyl)piperazine)

A mixture of 1-(4-nitrophenyl)piperazine (2.00 g, 9.7 mmol) (AcrosOrganics), powdered potassium carbonate (2.7 g, 19.3 mmol),2-bromopropane (0.96 mL, 10.1 mmol), potassium iodide (50 mg) and acatalytic amount of 18-crown-6 in acetonitrile (15 mL) was heated atreflux overnight. The mixture was filtered, and the filter cake waswashed with acetonitrile. The solvent was evaporated from the combinedfiltrates and the residue was partitioned between water and ethylacetate. The layers were separated and the aqueous layer was extractedtwice with ethyl acetate. The combined organic layers were washed withbrine, dried (MgSO4), filtered, evaporated and chromatographed (0-66%acetone/dichloromethane) to give1-(1-methylethyl)-4-(4-nitrophenylpiperazine) (1.7 g, 71%).

B. 4-[4-(1-Methylethyl)-1-piperazinyl]benzenamine

A mixture of 1-(1-methylethyl)-4-(4-nitrophenylpiperazine) (1.7 g, 6.8mmol) (from Step A above) and 10% palladium-on-charcoal in ethanol (30mL) was hydrogenated at room temperature and atmospheric pressureovernight. The catalyst was filtered off and the filter cake washedthoroughly with ethanol. The mixture was evaporated under reducedpressure to give 4-[4-(1-methylethyl)-1-piperazinyl]benzenamine (1.6 g,quantitative yield) as a dark brown oil.

C. 1-(4-Isothiocyanatophenyl)-4-(1-methylethyl)piperazine

A solution of 4-[4-(1-methylethyl)-1-piperazinyl]benzenamine (1.6 g,˜6.8mmol) (from Step B above) in N,N-dimethylformamide (25 mL) was addeddropwise over 20 min to a cooled (−15° C.) solution ofthiocarbonyidiimidazole (1.4 g, 7.7 mmol) (Aldrich) inN,N-dimethylformamide (30 mL). After the addition was complete, themixture was stirred at −15° C. for 20 min, then the cooling bath wasremoved and the solution was stirred for 1 h. Ice-water was added andthe mixture was extracted with ether. The ether layer was dried (MgSO4),filtered, and evaporated to give1-(4-isothiocyanatophenyl)-4-(1-methylethyl)piperazine (1.8 g,quantitative yield).

Example 4

1-(Acetyl)-4-(4-isothiocyanatophenyl)piperazine

This compound can be prepared by the procedure of Chong, W. K. et al.WO9921845, or as follows:

A. 1-Acetyl-4-(4-nitrophenyl)piperazine

Powdered potassium carbonate (276 mg, 2 mmol) and then acetyl chloride(0.14 mL, 2 mmol) were added to a solution of 1-(4-nitrophenyl)piperazine (2.1 g, 1 mmol) (Acros Organics) in dichloromethane (75 mL).The mixture was stirred at room temperature overnight and then furtherquantities of powdered potassium carbonate (500 mg, 3.6 mmol) and acetylchloride (0.2 mL, 2.8 mmol) were added. The mixture was stirred at roomtemperature overnight, then it was filtered and the filter cake waswashed with dichloromethane. The solvent was evaporated from thefiltrate, and the residue was chromatographed (0-66%acetone/dichloromethane) to give 1-acetyl-4-(4-nitrophenyl)piperazine(1.8 g, 72%).

B. 1-Acetyl-4-(4-aminophenyl)piperazine

A mixture of 1-acetyl-4-(4-nitrophenyl)piperazine (1.8 g, 7.2 mmol)(from Step A above) and 10% palladium-on-charcoal in ethanol (50 mL) washydrogenated at room temperature and atmospheric pressure overnight. Thecatalyst was filtered off and the filter cake washed thoroughly withethanol. The mixture was evaporated under reduced pressure to give1-acetyl-4-(4-amino-phenyl)piperazine (1.0 g, 63%) as an off-whitesolid.

C. 1-(Acetyl)-4-(4-isothiocyanatophenyl)piperazine

A solution of 1-acetyl-4-(4-aminophenyl)piperazine (1.0 g, 4.6 mmol)(from Step B above) in N,N-dimethylformamide (10 mL) was added dropwiseto a cooled (−15° C.) solution of thiocarbonyidiimidazole (855 mg, 4.8mmol) in N,N-dimethylformamide (10 mL). After the addition was complete,the mixture was stirred at −15° C. for 30 min, then the cooling bath wasremoved and the solution was stirred for 1 h. Ice-water was added andthe mixture was extracted with ether (4×50 mL). The combined etherlayers were washed with brine, dried (MgSO₄), filtered, and evaporatedto give 1-(acetyl)-4-(4-isothiocyanatophenyl)piperazine (1.0 g, 84%).

Example 5

4-(2-Hydroxyethyl)-1-(4-isothiocyanatophenyl)piperazine

This compound was prepared from 4-(4-nitrophenyl)-1-piperazine-ethanol(Bionet Research Ltd.) using the hydrogenation andisothiocyanate-forming reactions used in Example 4.

Example 6

4-(4-Isothiocyanatophenyl)-1-piperazinecarboxylic acid,1,1-dimethylethyl ester

A. 4-(4-Nitrophenyl)-1-piperazinecarboxylic acid, 1,1-dimethylethylester

1-(4-Nitrophenyl)piperazine (20 g, 96.5 mmol) (Acros Organics) wasdissolved in dioxane (300 mL), and diisopropylethylamine (13.7 g, 106mmol) (Aldrich) was added. To the solution was added di-tert-butyldicarbonate (21 g, 96.6 mmol). After stirring overnight, the mixture waspoured into water (1 L) and stirred for 10 minutes. The aqueous layerwas extracted with ethyl acetate (2×500 mL) and the combined organicextracts were dried over MgSO₄, filtered, and evaporated in vacuo. Theresidue was recrystalized from a mixture of ethyl acetate/hexane toprovide 4-(4-nitrophenyl)-1-piperazinecarboxylic acid, 1,1-dimethylethylester (22.7 g, 77%).

B. 4-(4-Aminophenyl)-1-piperazinecarboxylic acid, 1,1-dimethylethylester

4-(4-Nitrophenyl)-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester(20 g, 65 mmol) was dissolved in anhydrous ethanol (250 mL) and 10% Pd/C(1.8 g) was added. The mixture was stirred for 1.5 h under 10 psi ofhydrogen and filtered through a Celite pad. The pad was washed withethyl acetate (3×100 mL) and the combined solution was evaporated invacuo to yield 4-(4-aminophenyl)-1-piperazinecarboxylic acid,1,1-dimethylethyl ester (18 g, 98% yield).

C. 4-(4-Isothiocyanatophenyl)-1-piperazinecarboxylic acid,1,1-dimethylethyl ester

A solution of 4-(4-aminophenyl)-1-piperazinecarboxylic acid,1,1-dimethylethyl ester (15 g, 54.1 mmol) (from Step B above) inN,N-dimethyl-formamide (120 mL) was added dropwise to a cooled (−15° C.)solution of 1,1′-thiocarbonyldiimidazole (9.66 g, 54.2 mmol) (Aldrich)in N,N-dimethylformamide (40 mL). After the addition was complete, thecooling bath was removed and the solution was stirred for 1 h. Themixture was poured into ice-water (1 L), stirred for 30 minutes, andextracted with diethyl ether. The combined extracts were dried overNa₂SO₄, and evaporated in vacuo to provide4-(4-isothio-cyanatophenyl)-1-piperazinecarboxylic acid,1,1-dimethylethyl ester (18 g, 94%).

Example 7

2-Bromo-1-[4-(1-piperidinyl)phenyl]ethanone

A. 2,2-Dibromo-1-[4-(1-piperidinyl)phenyl]ethanone

Following the procedure of Diwu et al. (Tetrahedron Lett. 1998, 39,4987-4990), 1-[4-(1-piperidinyl)phenyl]ethanone (5 g, 24.6 mmol)(Aldrich) was dissolved in concentrated sulfuric acid (25 mL) and theresulting solution was cooled to 0° C. To the solution was slowly addedbromine (1.3 mL, 25.4 mmol) at 0° C. with stirring. The mixture wasgradually warmed to room temperature and stirred for 6h. The reactionmixture was poured into ice/water. The precipitate was collected byfiltration, washed with water and dried in vacuo to provide2,2-dibromo-1-[4-(1-piperidinyl)phenyl]ethanone (8.2 g, 93%).

B. 2-Bromo-1-[4-(1-piperidinyl)phenyl]ethanone

2,2-Dibromo-1-[4-(1-piperidinyl)phenyl]ethanone (3 g, 8.3 mmol) (fromStep A above) was dissolved in tetrahydrofuran (15 mL), and cooled to 0°C. To the resulting solution were added dropwise diethylphosphite (1.13mL, 8.7 mmol) and triethylamine (1.21 mL, 8.7 mmol) in tetrahydrofuran(7 mL) at 0° C. with stirring. The mixture was slowly warmed to roomtemperature and stirred for 6 h. The reaction mixture was concentratedin vacuo and poured into ice/water. The precipitate was collected byfiltration, washed with water and dried in vacuo to provide2-bromo-1-[4-(1-piperidinyl)phenyl]ethanone (2.3 g, 100% yield).

Example 8

2-Bromo-1-[4-(4-morpholinyl)phenyl]ethanone

This compound was prepared from 1-[4-(4-morpholinyl)phenyl]ethanone(Aldrich) by procedures analogous to those used to prepare2-bromo-1-[4-(1-piperidinyl)phenyl]ethanone (Example 7).

Example 9

2-Bromo-1-(3,5-dimethoxyphenyl)ethanone

A mixture of 1-(3,5-dimethoxyphenyl)ethanone (3.0 g, 16.6 mmol)(Aldrich) and copper(II) bromide (6.2 g, 27.8 mmol) (Aldrich) in ethylacetate (35 mL) was heated at reflux under argon for 5 h. Charcoal wasadded to the mixture which was stirred and then filtered throughCelite™. The filter cake was washed with ethyl acetate, and the combinedfiltrates were evaporated and then purified by elution withdichloromethane (500 mL) through silica gel (150 g) in a filter funnelto give crude 1-(3,5-dimethoxyphenyl)ethanone (4.9 g, quantitativeyield). This was used without further purification.

Example 10

N-[4-(Bromoacetyl)phenyl]acetamide

A solution of bromine (0.31 mL, 5.9 mmol) in carbon tetrachloride (10mL) was added to a suspension of N-(4-acetylphenyl)acetamide (1 g, 5.6mmol) (Lancaster Synthesis) in carbon tetrachloride (20 mL). Thereaction mixture was stirred for several hours but TLC indicated onlystarting material. Acetic acid (10 mL) was added, and the reactionmixture was stirred overnight. Filtration gaveN-[4-(bromoacetyl)phenyl]acetamide (1.4 g) as a solid. HPLC indicatedthat the purity was approximately 80%. This material was used directlyin subsequent steps without purification.

Example 11

1-(1,3-Benzodioxol-5-yl)-2-bromoethanone

Eight drops of a solution of bromine (1.95 g, 12.2 mmol) in benzene (10mL) were added to a solution of 1-(1,3-benzodioxol-5-yl)ethanone (2.00g, 12.2 mmol) (Acros Organics) in benzene (40 mL) in a flask protectedfrom light with aluminum foil. The solution was heated to reflux for ˜30seconds, but it did not decolorize. The rest of the bromine solution wasadded in ˜1 mL aliquots and the solution was then allowed to stand for 2h. Ethyl acetate (100 mL) was added, and the solution was washed withwater and saturated sodium bicarbonate solution (100 mL each), dried(MgSO₄), filtered and evaporated to give a black liquid that solidifiedon standing. NMR indicated that it was a ˜1:3 mixture of1-(1,3-benzodioxol-5-yl)-2,2-dibromoethanone and1-(1,3-benzodioxol-5-yl)-2-bromoethanone. This material was useddirectly in subsequent steps without purification.

Example 12

2-Bromo-1-(4-hydroxyphenyl)ethanone

To a solution of 4-hydroxyacetophenone (2.5 g, 18.3 mmol) (Aldrich) indioxane (10 mL) was added dropwise a solution of bromine (3.22 g, 20.1mmol) in dioxane (20 mL). After stirring for 10 minutes, the mixture wasconcentrated in vacuo and the residue was recrystalized from methanol toprovide 2-bromo-1-(4-hydroxyphenyl)ethanone (1.73 g, 44% yield).

Example 13

2-Bromo-1-(3-fluoro-4-methoxyphenyl)ethanone

To a solution of 3′-fluoro-4′-methoxyacetophenone (1 g, 5.9 mmol)(Aldrich) in dioxane (10 mL) was added dropwise a solution of bromine(1.13 g, 7.1 mmol) in dioxane (30 mL). After stirring for 10 minutes,the mixture was concentrated in vacuo and the residue was purified byflash chromatography, with 10:4 hexanes/dichloromethane as an eluant, toprovide 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethanone as a white powder(910 mg, 63% yield).

Example 14A

2-Bromo-1-(3,5-difluorophenyl)ethanone

To a solution of 3′,5′-difluoroacetophenone (3 g, 19.2 mmol) (LancasterSynthesis) in dioxane (30 mL) was added dropwise a solution of bromine(3.67 g, 23 mmol) in dioxane (75 mL). After stirring for 10 minutes, themixture was concentrated in vacuo and the residue was purified by flashchromatography, with 10:2 hexanes/dichloromethane as an eluant, toprovide 2-bromo-1-(3,5-difluorophenyl)ethanone as a colorless oil (2.9g, 64% yield).

Example 14B

1-(4-Isothiocyanatophenyl)-4-(2-methoxy-ethyl)piperazine

A. 1-(1-[2-methoxy-ethyl])-4-(4-nitrophenyl)piperazine)

A mixture of 4-chloronitrobenene (5.5 g, 34.9 mmol) (Aldrich), and1-(2-methoxy-ethyl)piperazine 5 g, 34.6 mmol (Chess, GmbH) was heated at80° C. overnight. Dichloromethane (100 mL) was added and washed withwater (3×100 mL). The organic layer was dried (Na2SO4) and concentratedto a dark red oil. Chromatography (4% methanol in dichloromethane)followed by recrystalization from ethyl acetate/hexane gave1-(1-[2-methoxy-ethyl])-4-(4-nitrophenyl)piperazine) (5.36 g, 58%)

B. 4-[4-(2-methoxy-ethyl)-1-piperazinyl]benzenamine

A mixture of 1-(1-]2-methoxy-ethyl]-4-(4-nitrophenyl)piperazine) (5.36g, 20.2 mmol) (from Step A above) and 10% palladium-on-charcoal inethanol (125 mL) was hydrogenated at room temperature at 20 psi for onehour. The catalyst was filtered off and the filter cake washedthoroughly with ethanol. The mixture was evaporated under reducedpressure to give 4-[4-(2-methoxy-ethyl)-1-piperazinyl]benzenamine (4 g,84%)

C. 1-(4-Isothiocyanatophenyl)-4-(1-[2-methoxy-ethyl])piperazine

A solution of 4-[4-(1-{2-methoxy-ethyl])-1-piperazinyl]benzenamine (4 g,17 mmol) (from Step B above) in N,N-dimethylformamide (60 mL) was addeddropwise over 20 min to a cooled (−15° C.) solution ofthiocarbonyidiimidazole (3 g, 17.03 mmol) (Aldrich) inN,N-dimethylformamide (15 mL). After the addition was complete, themixture was stirred at −15° C. for 20 min, then the cooling bath wasremoved and the solution was stirred for 1 h. Ice-water (800 ml) wasadded and the mixture was stirred for 30 min. The solid was filtered offand washed with water and dried under vacuum to give1-(4-isothiocyanatophenyl)-4-(1-[2-methoxy-ethyl])piperazine (2.8 g,67%).

Example 14C

1-(4-Isothiocyanatophenyl)-4-(1-methylpropyl)piperazine

A. 1-(sec-butyl)-4-(4-nitrophenyl)piperazine)

A mixture of 1-(4-nitrophenyl)piperazine (6, 28.98 mmol) (AcrosOrganics), powdered potassium carbonate (2.7 g, 30.4 mmol),2-Bromobutane (3.32 ml, 30.4 mmol), and a catalytic amount of 18-crown-6in acetonitrile (45 mL) was heated at reflux overnight. The mixture wasfiltered, and the filter cake was washed with acetonitrile. The solventwas evaporated from the combined filtrates and the residue waspartitioned between water and ethyl acetate. The layers were separatedand the aqueous layer was extracted twice with ethyl acetate. Thecombined organic layers were dried (Na2SO4), filtered, evaporated andchromatographed (2.5% methanol in dichloromethane) to give1-(sec-butyl)-4-(4-nitrophenylpiperazine) (4.45 g, 58%).

B. 4-[4-(sec-butyl)-1-piperazinyl]benzenamine

A mixture of 1-(sec-butyl)-4-(4-nitrophenylpiperazine) (4.45 g, 16.9mmol) (from Step A above) and 10% palladium-on-charcoal in ethanol (125mL) was hydrogenated at room temperature at 20 psi for 1.25 hour. Thecatalyst was filtered off and the filter cake washed thoroughly withethanol. The mixture was evaporated under reduced pressure to give4-[4-(sec-butyl)-1-piperazinyl]benzenamine (3.55g g, 90%)

C. 1-(4-Isothiocyanatophenyl)-4-(sec-butyl)piperazine

A solution of 4-[4-(sec-butyl)-1-piperazinyl]benzenamine (3.5 g, 15mmol) (from Step B above) in N,N-dimethylformamide (40 mL) was addeddropwise over 20 min to a cooled (−15° C.) solution ofthiocarbonyidiimidazole (2.68 g, 15.03 mmol) (Aldrich) inN,N-dimethylformamide (15 mL). After the addition was complete, themixture was stirred at −15° C. for 20 min, then the cooling bath wasremoved and the solution was stirred for 1 h. Ice-water (800 ml) wasadded and the mixture was stirred for 30 min. The solid was filtered offand washed with water and dried under vacuum to give1-(4-isothiocyanatophenyl)-4-(sec-butyl)piperazine (3.6 g, 87%) as apurple solid.

Example 14D

4-Cyclopentyl-1-(4-isothiocyanatophenyl)piperazine

A. 1-Cyclopentyl-4-(4-nitrophenyl)piperazine)

A mixture of 1-(4-nitrophenyl)piperazine (12 g, 57.9 mmol) (AcrosOrganics), powdered potassium carbonate (5.4 g, 39 mmol),iodocyclopentane(7 mL, 60.8 mmol) (Aldrich) and a catalytic amount of18-crown-6 in acetonitrile (90 mL) was heated at reflux overnight. Themixture was filtered, and the filter cake was washed with acetonitrile.The solvent was evaporated from the combined filtrates and the residuewas partitioned between water and ethyl acetate. The layers wereseparated and the aqueous layer was extracted twice with ethyl acetate.The combined organic layers were dried (Na2SO4), filtered, evaporated toa yellow solid and dried under vacuum to give1-cyclopentyl-4-(4-nitrophenyl)piperazine) (6.6 g, 41%.)

B. 4-(4-Cyclopentyl-1-piperazinyl)benzenamine

A mixture of 1-cyclopentyl-4-(4-nitrophenylpiperazine) (6.6 g, 23.9mmol) (from Step A above) and 10% palladium-on-charcoal in ethanol (175mL) was hydrogenated at room temperature at 20 psi for 1.25 hr. Thecatalyst was filtered off and the filter cake washed thoroughly withethanol. The mixture was evaporated under reduced pressure to give4-(4-cyclopentyl-1-piperazinyl)benzenamine (5.7 g, 97%)

C. 4-Cyclopentyl-1-(4-isothiocyanatophenyl)piperazine

A solution of 4-[4-(1-cyclopentyl)-1-piperazinyl]benzenamine (5.7 g,22.4 mmol) (from Step B above) in N,N-dimethylformamide (75 mL) wasadded dropwise over 20 min to a cooled (−15° C.) solution ofthiocarbonyldiimidazole (4 g, 22.5 mmol) (Aldrich) inN,N-dimethylformamide (40 mL). After the addition was complete, themixture was stirred at −15° C. for 20 min, then the cooling bath wasremoved and the solution was stirred for 1 hr. then poured intoice-water (1500 mL), stirred for 30 min. then the precipitate filteredand washed with water and dried under vacuum to give4-cyclopentyl-1-(4-isothiocyanatophenyl)piperazine (6 g, 93%)

Example 14E

1-(4-Isothiocyanatophenyl)-4-(2-methylpropyl)piperazine

A. 1-(isobutyl)-4-(4-nitrophenyl)piperazine)

A mixture of 1-(4-nitrophenyl)piperazine (8 g, 38.6 mmol) (AcrosOrganics), powdered potassium carbonate (3.58 g, 25.98 mmol),1-lodo-2-methylpropane (4.66 ml, 40.5 mmol), and a catalytic amount of18-crown-6 in acetonitrile (60 mL) was heated at reflux overnight. Themixture was filtered, and the filter cake was washed with acetonitrile.The solvent was evaporated from the combined filtrates and the residuewas partitioned between water and ethyl acetate. The layers wereseparated and the aqueous layer was extracted twice with ethyl acetate.The combined organic layers were dried (Na2SO4), filtered, evaporatedand dried under vacuum to give 1-(isobutyl)-4-(4-nitrophenyl)piperazine)(9.4 g, 92%) as a yellow solid.

B. 4-[4-(isobutyl)-1-piperazinyl]benzenamine

A mixture of 1-(isobutyl)-4-(4-nitrophenylpiperazine) (9.4 g, 35.7 mmol)(from Step A above) and 10% palladium-on-charcoal in ethanol (175 mL)was hydrogenated at room temperature at 20 psi for 1.25 hour. Thecatalyst was filtered off and the filter cake washed thoroughly withethanol. The mixture was evaporated under reduced pressure to give4-[4-(isobutyl)-1-piperazinyl]benzenamine (7.8 g, 94%) as a dark redsolid.

C. 1-(4-Isothiocyanatophenyl)-4-(1-isobutyl)piperazine

A solution of 4-[4-(isobutyl)-1-piperazinyl]benzenamine (7.8 g, 33.4mmol) (from Step B above) in N,N-dimethylformamide (75 mL) was addeddropwise over 20 min to a cooled (−15° C.) solution ofthiocarbonyldiimidazole (5.97 g, 33.5 mmol) (Aldrich) inN,N-dimethylformamide (25 mL). After the addition was complete, themixture was stirred at −15° C. for 20 min, the cooling bath was removedand the solution was stirred for 1 h. Ice-water (700 ml) was added andthe mixture was stirred for 30 min. The solid was filtered off andwashed with water and dried under vacuum to give1-(4-Isothiocyanatophenyl)-4-(1-isobutyl)piperazine (8 g, 87%)

Example 14F

4-(3-Hydroxypropyl)-1-(4-isothiocyanatophenyl)piperazine

This compound was prepared from 4-(4-nitrophenyl)-1-piperazine-propanol(which can be prepared according to the procedure of Loewe and MiethArzneim.-Forsch. 1966, 16, 1306-1310) using the hydrogenation andisothiocyanate-forming reactions used in Example 4. MS (ES) MH⁺=277.

Example 14G

4-Cyclopropylmethyl-1-(4-isothiocyanatophenyl)piperazine

A. 1-(Cyclopropylmethyl)-4-(4-nitrophenyl)piperazine)

A mixture of 1-(4-nitrophenyl)piperazine (10 g, 48.3 mmol) (AcrosOrganics), powdered potassium carbonate (4.5 g, 32.6 mmol),Cyclopropylmethyl bromide (4.93 ml, 50.7 mmol), and a catalytic amountof 18-crown-6 in acetonitrile (75 mL) was heated at reflux overnight.The mixture was filtered, and the filter cake was washed withacetonitrile. The solvent was evaporated from the combined filtrates andthe residue was partitioned between water and ethyl acetate. The layerswere separated and the aqueous layer was extracted twice with ethylacetate. The combined organic layers were washed with brine, dried(Na2SO4), filtered, evaporated and chromatographed (4% methanol indichloromethane) to give1-(cyclopropylmethyl)-4-(4-nitrophenylpiperazine) (4.27 g, 34%).

B. 4-[4-(Cyclopropylmethyl)-1-piperazinyl]benzenamine

A mixture of 1-(cyclopropylmethyl)-4-(4-nitrophenylpiperazine) (4.27 g,16.3 mmol) (from Step A above) and 10% palladium-on-charcoal in ethanol(125 mL) was hydrogenated at room temperature at 20 psi for one hour.The catalyst was filtered off and the filter cake washed thoroughly withethanol. The mixture was evaporated under reduced pressure to give4-[4-(cyclopropylmethyl)-1-piperazinyl]benzenamine (3.7 g g, 98%) as adark red solid.

C. 1-(4-Isothiocyanatophenyl)-4-(1-cyclopropylmethyl)piperazine

A solution of 4-[4-(cyclopropylmethyl)-1-piperazinyli]benzenamine (3.7g, 16 mmol) (from Step B above) in N,N-dimethylformamide (50 mL) wasadded dropwise over 20 min to a cooled (−15° C.) solution ofthiocarbonyidiimidazole (2.87 g, 16.1 mmol) (Aldrich) inN,N-dimethylformamide (25 mL). After the addition was complete, themixture was stirred at −15° C. for 20 min, then the cooling bath wasremoved and the solution was stirred for 1 h. Ice-water (1000 mL) wasadded and the mixture was stirred for 30 min. The solid was filtered offand washed with water and dried under vacuum. (4 g, 91%).

Example 14H

2-Bromo-1-(3,4,5-trifluoro-phenyl)ethanone

This compound was prepared from 1-(3,4,5-trifluoro-phenyl)ethanone (ABCRGmbH & Co. KG) following the procedure used in Example 13.

Example 14I

2-Bromo-1-(4-fluoro-3-methoxy-phenyl)ethanone

This compound was prepared from 1-(4-fluoro-3-methoxy-phenyl)ethanone(Apin Chemicals Ltd.) following the procedure used in Example 13.

Example 14J

2-Bromo-1-(3-trifluoromethoxy-phenyl)ethanone

This compound was prepared from 1-(3-trifluoromethoxy-phenyl)ethanone(Aldrich) following the procedure used in Example 13.

Example 14K

2-Bromo-1-(3,5-difluoro4-methoxy-phenyl)ethanone

This compound was prepared from1-(3,5-difluoro-4-methoxy-phenyl)ethanone (ABCR GmbH & Co. KG) followingthe procedure used in Example 13.

Example 14L

2-Bromo-1-(3-difluoromethoxy-phenyl)ethanone

This compound was prepared from 1-(3-difluoromethoxy-phenyl)ethanone(ABCR GmbH & Co. KG) following the procedure used in Example 13.

Example 14M

2-Bromo-1-(4-hydroxy-3-fluoro-phenyl)ethanone

This compound was prepared from 1-(4-hydroxy-3-fluoro-phenyl)ethanone(Apin Chemicals Ltd.) following the procedure used in Example 13.

Example 14N

2-Bromo-1-(3-hydroxy-phenyl)ethanone

This compound was prepared from 1-(3-hydroxy-phenyl)ethanone (Aldrich)following the procedure used in Example 13.

Example 14O

2-Bromo-1-(3-ethylphenyl)ethanone

To a stirred solution of 3-ethylacetophenone (Maybridge Chemical CompanyLtd.; 1.103 9, 7.44 mmol) in dry 1,4-dioxane (15 mL) was added bromine(383 μL, 7.44 mmol). The solution was stirred at room temperature for 30min. and then the solvent was removed on a rotary evaporator. Theresidue was chromatographed on a Foxy 200 machine (Isco, Inc., P.O. Box82531, Lincoln, Nebr. 68501, USA.; eluent, 5% CH₂Cl₂/Hexane, 0-2 min.then 20-30% CH₂Cl₂/Hexane, 2-20 min.) to give2-bromo-1-(3-ethylphenyl)ethanone (1.15 g, 68%) as a clear oil.

Example 15

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](4-chloro-3-nitrophenyl)methanone

To a mixture of 1-(4-isothiocyanatophenyl)-4-methylpiperazine (ofExample 1; 1.0 g, 4.3 mmol) and cyanamide (0.2 g, 4.8 mmol) inacetonitrile (43 mL), a solution of potassium tert-butoxide (43 mL, 0.1M in tert-BuOH) was added. After 30 minutes at room temperature,2-bromo-1-(4-chloro-3-nitro-phenyl)ethanone (1.2 g, 4.3 mmol) (MaybridgeChemical Company Ltd.) was added. The reaction mixture was stirred for4h and then poured into 50 mL of water. The product was collected byfiltration, washed with water and diethyl ether. The yellow powder wasdried in vacuo to provide 0.9 g (45% yield) of[4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](4-chloro-3-nitrophenyl)methanone.

Example 16

Resin-bound Thiouronium Salt

Following the procedure of Obrecht et al. (Helv. Chim. Acta. 1997, 80,65-72), a mixture of Merrifield resin (77 g, 331 mmol: Cl load of 4.3mmol/g) (Fluka) and thiourea (126 g, 1650 mmol) in dioxane/ethanol (4/1)(750 mL) was heated at 85° C. for 5 days. The reaction mixture wasfiltered and the resin was successively washed with hot ethanol (2×500mL), ethanol (500 mL), dioxane (2×500 mL), hexanes (2×500 mL) anddiethyl ether (2×500 mL). The pale yellow resin was dried in vacuo toafford 115 g of the title resin. The loading of the resin was determinedby nitrogen and sulfur analysis: N (7.78), S (9.77).

Example 17

Resin-bound Thiourea: General Procedure

A mixture of resin-bound thiouronium salt (of Example 16; 1 g, 2.8 mmol,loading capacity: 2.8 mmol/g), isothiocyanate (R¹NCS), 5.6 mmol),N,N-diisopropylethylamine (5.6 mmol) (Aldrich), and resin-boundN,N-diisopropyl-ethylamine (5.6 mmol, loading capacity: 3.59 mmol/g fromArgonaut, Inc.) in N,N-dimethylformamide (12 mL) was gently shakenovernight. The resin was filtered and washed successively withN,N-dimethylformamide, THF, MeOH, CH₂Cl₂, and diethyl ether. The resinwas dried at 40° C./high vacuum overnight to provide resin-boundthiourea.

The following resin-bound thioureas were prepared from the indicatedisothiocyanates using the general procedure described in Example 17.

Starting Material: Isothiocyanate (R¹NCS) Product: Resin-bound thiourea

Example 1 Example 18

Example 2 Example 19

Example 3 Example 20

Example 4 Example 21

Example 5 Example 22

Example 6 Example 23A

Example 14B Example 23B

Example 14C Example 23C

Example 14D Example 23D

Example 14E Example 23E

Example 14F Example 23F

Example 24

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](2,3-dihydro-1,4-benzodioxin-6-yl)methanone

tert-Butanol (4 mL) and then 1-(4-isothiocyanatophenyl)-4-methylpiperazine (of Example 1; 219 mg, 1 mmol) were added to a solution ofcyanamide (44 mg, 1.05 mmol) (Aldrich) in acetonitrile (5 mL). Potassiumt-butoxide (1 M in tert-butanol; 1 mL, 1 mmol) was added and thesolution was stirred for 30 min.2-Bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethanone (257 mg, 1 mmol)(Maybridge Chemical Company Ltd.) was added, and the solution wasstirred at room temperature for 3 days. The yellow solid was filteredoff and washed with cold acetonitrile and then ether to give[4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](2,3-dihydro-1,4-benzodioxin-6-yl)methanone(280 mg, 66%).

Example 25

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](1,3-benzodioxol-5-yl)methanone

This compound was prepared in 75% yield from cyanamide (Aldrich),1-(4-isothiocyanatophenyl)-4-methylpiperazine (of Example 1), and1-(1,3-benzodioxol-5-yl)-2-bromoethanone (of Example 11) following theprocedure used to in Example 24.

Example 26

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(1-pyrrolidinyl)phenyl]methanone

tert-Butanol (4 mL) and then 1-(4-isothiocyanatophenyl)-4-methylpiperazine (of Example 1; 219 mg, 1 mmol) were added to a solution ofcyanamide (44 mg, 1.05 mmol) in acetonitrile (5 mL). Potassiumt-butoxide (1 M in tert-butanol; 1 mL, 1 mmol) was added and thesolution was stirred for 30 min.2-Bromo-1-[4-(1-pyrrolidinyl)phenyl]ethanone (257 mg, 1 mmol)(Lancaster) was added, and the solution was stirred at room temperaturefor 2 days. The yellow-brown solid was filtered off and washed with coldacetonitrile, water and then cold acetonitrile (weight of solid: 271mg). A portion of this crude product (50 mg) was purified bychromatography (10% methanol/dichloromethane) to give[4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(1-pyrrolidinyl)phenyl]methanone(18.5 mg).

Example 27

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(1-piperidinyl)phenyl]methanone

A mixture of the resin-bound thiourea of Example 18 (57 mg, 0.1 mmol,loading capacity: 1.76 mmol/g) and2-bromo-1-[4-(1-piperidinyl)phenyl]ethanone (of Example 7; 56 mg, 0.2mmol) in N,N-dimethylformamide (1.5 mL) was shaken overnight. Thereaction suspension was filtered and the resin was washed withN,N-dimethylformamide and dichloromethane. The solvent was evaporated invacuo and the residue was triturated by diethyl ether/hexanes (1/9) toyield[4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(1-piperidinyl)phenyl]methanone. Mass spectrum (ES) MH⁺=477.

Example 28

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(4-morpholinyl)phenyl]methanone,Acetate Salt

This compound was prepared from the resin-bound thiourea of Example 18and 2-bromo-1-[4-(4-morpholinyl)phenyl]ethanone (of Example 8) by theprocedure used in Example 27. The crude product was purified by HPLCusing an Amicon C₁₈ 2×5 cm column with the following gradient: A (20 mMNH₄OAc/H₂O), B (20 mM NH₄OAc/CH₃CN), A to B gradient (10 to 75% over 10minutes), flow rate: 20 mL/min. Mass spectrum (ES) MH⁺=479.

Example 29

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3,4-dihydro-2H-1,5-benzodioxepin-7-yl)methanone

This compound was prepared from the resin-bound thiourea of Example 18and 2-bromo-1-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)ethanone (MaybridgeChemical Company Ltd.) by the procedure used in Example 27. Massspectrum (ES) MH⁺=466.

Example 30

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl]-(4-hydroxyphenyl)methanone

This compound was prepared from the resin-bound thiourea of Example 18and 2-bromo-1-(4-hydroxyphenyl)ethanone (of Example 12) by the procedureused in Example 27. Mass spectrum (ES) MH⁺=410.

Example 31

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3-nitrophenyl)methanone

This compound was prepared from the resin-bound thiourea of Example 18and 2-bromo-1-(3-nitrophenyl)ethanone (Aldrich) by the procedure used inExample 27. Mass spectrum (ES) MH⁺=439.

Example 32

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](4-methoxyphenyl)methanone

This compound was prepared from the resin-bound thiourea of Example 18and 2-bromo-1-(4-methoxyphenyl)ethanone (Aldrich) by the procedure usedin Example 27. Mass spectrum (ES) MH⁺=424.

Example 33

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(diethylamino)phenyl]methanone

This compound was prepared from the resin-bound thiourea of Example 18and 2-bromo-1-[4-(diethylamino)phenyl]ethanone (Lancaster Synthesis) bythe procedure used in Example 27. Mass spectrum (ES) MH⁺=465.

Example 34

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](2-dibenzofuranyl)methanone

This compound was prepared from the resin-bound thiourea of Example 18and 2-bromo-1-(2-dibenzofuranyl)ethanone (Salor), by the procedure usedin Example 27. Mass spectrum (ES) MH⁺=484.

Example 35

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3-fluoro-4-methoxyphenyl)methanone

This compound was prepared from the resin-bound thiourea of Example 18and 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethanone (of Example 13) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=442.

Example 36

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3-methoxyphenyl)methanone

This compound was prepared from the resin-bound thiourea of Example 18and 2-bromo-1-(3-methoxyphenyl)ethanone (Aldrich) by the procedure usedin Example 27. Mass spectrum (ES) MH⁺=424.

Example 37

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3,4-dichlorophenyl)methanone

This compound was prepared from the resin-bound thiourea of Example 18and 2-bromo-1-(3,4-dichlorophenyl)ethanone (Lancaster Synthesis) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=462.

Example 38

[4-Amino-2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](1,3-benzodioxol-5-yl)methanone

This compound was prepared from the resin-bound thiourea of Example 19and 1-(1,3-benzodioxol-5-yl)-2-bromoethanone (of Example 11) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=456.

Example 39

[4-Amino-2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3,5-dimethoxyphenyl)methanone

This compound was prepared from the resin-bound thiourea of Example 19and 2-bromo-1-(3,5-dimethoxyphenyl)ethanone (of Example 9) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=472.

Example 40

[4-Amino-2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3-methoxyphenyl)methanone

This compound was prepared from the resin-bound thiourea of Example 19and 2-bromo-1-(3-methoxyphenyl)ethanone (Aldrich) by the procedure usedin Example 27. Mass spectrum (ES) MH⁺=442.

Example 41

[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](2,3-dihydro-1,4-benzodioxin-6-yl)methanone

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethanone (MaybridgeChemical Company Ltd.) by the procedure used in Example 27. Massspectrum (ES) MH⁺=480.

Example 42

[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](1,3-benzodioxol-5-yl)methanone

This compound was prepared from the resin-bound thiourea of Example 20and 1-(1,3-benzodioxol-5-yl)-2-bromoethanone (of Example 11) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=466.

Example 43

[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](3-methoxyphenyl)methanone

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-(3-methoxyphenyl)ethanone (Aldrich) by the procedure usedin Example 27. Mass spectrum (ES) MH⁺=452.

Example 44

[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](3,5-dimethoxyphenyl)methanone

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-(3,5-dimethoxyphenyl)ethanone (of Example 9) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=482.

Example 45

[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl]carbonyl]phenyl]acetamide

This compound was prepared from the resin-bound thiourea of Example 20and N-[4-(bromoacetyl)phenyl]acetamide (of Example 10) by the procedureused in Example 27. Mass spectrum (ES) MH⁺=479.

Example 46

[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl][4-(diethylamino)phenyl]methanone

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-[4-(diethylamino)phenyl]ethanone (Lancaster Synthesis) bythe procedure used in Example 27. Mass spectrum (ES) MH⁺=493.

Example 47

1-Acetyl-4-[4-[[4-amino-5-[(1,3-benzodioxol-5-yl)carbonyl]-2-thiazolyl]amino]phenyl]piperazine

This compound was prepared from the resin-bound thiourea of Example 21and 1-(1,3-benzodioxol-5-yl)-2-bromoethanone (of Example 11) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=466.

Example 48

1-Acetyl-4-[4-[[4-amino-5-[4-(diethylamino)benzoyl]-2-thiazolyl]amino]phenyl]piperazine,trifluoroacetate salt

This compound was prepared from the resin-bound thiourea of Example 21and 2-bromo-1-[4-(diethylamino)phenyl]ethanone (Lancaster Synthesis) bythe procedure used in Example 27. The crude product was purified by HPLCusing an Amicon C₁₈ 2×5 cm column with the following gradient: A (0.05%TFA/H₂O), B (0.05% TFA/CH₃CN), A to B gradient (10 to 75% over 10minutes), flow rate: 20 mL/min. Mass spectrum (ES) MH⁺=493.

Example 49

[4-Amino-2-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](2,3-dihydro-1,4-benzodioxin-6-yl)methanone

This compound was prepared from the resin-bound thiourea of Example 22and 2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethanone (MaybridgeChemical Company Ltd.) by the procedure used in Example 27. Massspectrum (ES) MH⁺=482.

Example 50

[4-Amino-2-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl][4-(1-pyrrolidinyl)phenyl]methanone

This compound was prepared from the resin-bound thiourea of Example 22and 2-bromo-1-[4-(1-pyrrolidinyl)phenyl]ethanone (Lancaster Synthesis)by the procedure used in Example 27. Mass spectrum (ES) MH⁺=493.

Example 51

4-Amino-2-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](3-fluorophenyl)methanone

This compound was prepared from the resin-bound thiourea of Example 22and 2-bromo-1-(3-fluorophenyl)ethanone (Maybridge Chemical Company Ltd.)by the procedure used in Example 27. Mass spectrum (ES) MH⁺=442.

Example 52

[4-Amino-2-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](3,5-difluorophenyl)methanone

This compound was prepared from the resin-bound thiourea of Example 22and 2-bromo-1-(3,5-difluorophenyl)ethanone (of Example 14) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=460.

Example 53

[4-Amino-2-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](3-methoxyphenyl)methanone

This compound was prepared from the resin-bound thiourea of Example 22and 2-bromo-1-(3-methoxyphenyl)ethanone (Aldrich) by the procedure usedin Example 27. Mass spectrum (ES) MH⁺=454.

Example 54

[4-Amino-2-[[4-(1-piperazinyl)phenyl]amino]-5-thiazolyl](3-fluorophenyl)methanone

A.4-[4-[[4-Amino-5-(3-fluorobenzoyl)-2-thiazolyl]amino]phenyl]-1-piperazine-carboxylacid, 1,1-dimethylethyl ester

This compound was prepared from the resin-bound thiourea of Example 23Aand 2-bromo-1-(3-fluorophenyl)ethanone (Maybridge Chemical Company Ltd.)by the procedure used in Example 27.

B.[4-Amino-2-[[4-(1-piperazinyl)phenyl]amino]-5-thiazolyl](3-fluorophenyl)methanone

A mixture of4-[4-[[4-amino-5-(3-fluorobenzoyl)-2-thiazolyl]amino]phenyl]-1-piperazinecarboxylicacid, 1, 1-dimethylethyl ester (75 mg, 0. 15 mmol) (from Step A above)and a solution of TFA/CH₂Cl₂ (1:1; 1.5 mL) was gently shaken for 1.5 h.The solution was evaporated in vacuo. To the residue was addedresin-bound N,N-diisopropylethylamine (2.5 g, loading capacity: 3.8mmol/g from Argonaut, Inc.) and CH₂Cl₂ (15 mL). After shaking overnight,the mixture was filtered and washed successively with CH₃OH and CH₂Cl₂.The solvent was evaporated in vacuo and the residue was triturated bydiethyl ether/hexanes (1/9) to afford[4-amino-2-[[4-(1-piperazinyl)phenyl]amino]-5-thiazolyl](3-fluorophenyl)methanone(60 mg, 100%).

Example 55

[4-Amino-2-[[4-(1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(1-pyrrolidinyl)phenyl]methanone

This compound was prepared from the resin-bound thiourea of Example 23Aand 2-bromo-1-[4-(1-pyrrolidinyl)phenyl]ethanone (Lancaster Synthesis)by the procedures used in Example 54. Mass spectrum (ES) MH⁺=449.

Example 56

[4-Amino-2-[[4-(1-piperazinyl)phenyl]amino)-5-thiazolyl](3-fluoro-4-methoxyphenyl)methanone

This compound was prepared from the resin-bound thiourea of Example 23Aand 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethanone (of Example 13) by theprocedures used in Example 54. Mass spectrum (ES) MH⁺=428.

Example 57

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(2-hydroxyethyl)amino-3-nitrophenyl]methanone

A mixture of[4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](4-chloro-3-nitrophenyl)methanone(of Example 15; 0.25 g, 0.53 mmol), ethanolamine (0.13 mL, 2.12 mmol),N,N-diisopropylethylamine (Aldrich) (0.37 mL, 2.12 mmol) in n-butanol(10 mL) was heated at 100° C. overnight. The solvent was evaporated invacuo and the residue was chromatographed on silica gel usingMeOH/CH₂Cl₂ (1/9) as the eluent to afford 73 mg (28% yield) of the titlecompound. Mass spectrum (ES) MH⁺=498.

Example 58

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-(1-pyrrolidinyl)phenyl]methanone

This compound was prepared from the compound of Example 15 andpyrrolidine by the procedure used in Example 57. Mass spectrum (ES)MH⁺=508.

Example 59

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-(4-morpholinyl)phenyl]methanone

This compound was prepared from the compound of Example 15 andmorpholine by the procedure used in Example 57. Mass spectrum (ES)MH⁺=524.

Example 60

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-[(2-methoxyethyl)amino]phenyl]methanone

This compound was prepared from the compound of Example 15 and2-methoxyethanamine (Aldrich) by the procedure used in Example 57. Massspectrum (ES) MH⁺=512.

Example 61

racemic[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-[3-(hydroxymethyl)-1-piperidinyl]phenyl]methanone

This compound was prepared from the compound of Example 15 and racemic3-piperidinemethanol (Aldrich) by the procedure used in Example 57. Massspectrum (ES) MH⁺=552.

Example 62

racemic[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-(2-methyl-1-pyrrolidinyl)phenyl]methanone

This compound was prepared from the compound of Example 15 and racemic2-methylpyrrolidine (Alfa Aesar) by the procedure used in Example 57.Mass spectrum (ES) MH⁺=522.

Example 63

(R)-[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-[[1-(hydroxymethyl)-3-methylbutyl]amino]phenyl]methanone

This compound was prepared from the compound of Example 15 and(R)-2-amino-4-methyl-1-pentanol (Aldrich) by the procedure used inExample 57. Mass spectrum (ES) MH⁺=554.

Example 64

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-(4-hydroxy-1-piperidinyl)phenyl]methanone

This compound was prepared from the compound of Example 15 and4-piperidinol (Aldrich) by the procedure used in Example 57. Massspectrum (ES) MH⁺=538.

Example 65

[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-amino-4-(4-pyrrolidinyl)phenyl]methanone

A solution of[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-(1-pyrrolidinyl)phenyl]methanone(of Example 58; 0.16 g, 0.32 mmol), NH₂NH₂ (2 mL), 10% Pd/C (5 mg), and2-propanol (12 mL) was heated at reflux for 1 h. The mixture wasfiltered through a Celite™ pad and concentrated in vacuo. Flashchromatography with 4:1 dichloromethane/methanol furnished[4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-amino-4-(4-pyrrolidinyl)phenyl]methanone(91 mg, 61% yield).

Example 66

(R)-[3-Amino-4-[[1-(hydroxymethyl)-3-methylbutyl]amino]phenyl][4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl]methanone

A solution of(R)-[4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyi][3-nitro-4-[[1-(hydroxymethyl)-3-methylbutyl]amino]phenyl]methanone(of Example 63; 30 mg, 0.05 mmol), NH₂NH₂ (0.5 mL), 10% Pd/C (5 mg), and2-propanol (2 mL) was heated at reflux for 1 h. The mixture was filteredthrough a Celite™ pad and concentrated in vacuo. Flash chromatographywith 4:1 dichloromethane/methanol furnished(R)-[3-amino-4-[[1-(hydroxymethyl)-3-methylbutyl]amino]phenyl][4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl]methanone(15 mg, 53% yield).

Example 67

[4-Amino-2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](2,3-dihydro-1,4-benzodioxin-5-yl)methanone

This compound was prepared from the resin-bound thiourea of Example 19and 2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethanone (MaybridgeChemical Company Ltd.) by the procedure used in Example 27. Massspectrum (ES) MH⁺=470.

Example 68

[4-Amino-2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(1-pyrrolidinyl)phenyl]methanone

This compound was prepared from the resin-bound thiourea of Example 19and 2-bromo-1-[4-(1-pyrrolidinyl)phenyl]ethanone (Lancaster) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=481.

Example 69

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-methoxy-phenyl)-methanone(with phosphoric acid)

A solution of{4-amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-methoxy-phenyl)-methanone(of Example 43; 113 mg, 0.25 mmol) was dissolved in hot ethanol (10 ml)and to this was added 25 mg of phosphoric acid in ethanol (1 ml). Thiswas cooled and crystals were collected and dried to furnish{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-methoxy-phenyl)-methanone;compound with phosphoric acid. MicroAnalysis C, H, N, P, and S.

Example 70

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}(3methylsulfanyl-phenyl)-methanone

To a mixture of 1-(4-isothiocyanatophenyl)-4-methylpiperazine (ofExample 1; 0.466 g, 2.0 mmol) and cyanamide (0.088 g, 2.1 mmol) inacetonitrile (3 mL) and t-butanol (5 ml), a solution of potassiumtert-butoxide (2.0 mL, 1.0 M in tert-BuOH) was added. After 30 minutesat room temperature, 2-bromo-1-(3-methylsulfanyl-phenyl)ethanone (whichcan be prepared by the procedure of Rogers, N. H. et. al. EP 87953; 0.49g, 2.0 mmol) was added. The reaction mixture was stirred at roomtemperature for 1 hour and then refluxed for 15 minutes. The cooledmixture was diluted with ethyl acetate and washed in turn with saturatedaqueous sodium carbonate and brine. The dried (sodium sulfate) solutionwas evaporated and the residue chromatographed on silica gel. Elution ofthe desired product with 9:1 dichloromethane/methanol andcrystallization from ethyl acetate/hexane provided 0.439 g (50% yield)of[4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazoly](3-methylsulfanyl-phenyl)methanone.Mass spectrum (ES) MH⁺=440.

Example 71

(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-fluoro-phenyl)-methanone

This compound was prepared from the resin-bound thiourea of Example 23Fand 2-bromo-1-(3-fluorophenyl)ethanone (Maybridge Chemical Company Ltd.)by the procedure used in Example 27. Mass spectrum (ES) MH⁺=456.

Example 72

(4-Amino-2-(4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-methoxy-phenyl)-methanone

This compound was prepared from the resin-bound thiourea of Example 23Fand 2-bromo-1-(3-methoxyphenyl)ethanone (Aldrich) by the procedure usedin Example 27. Mass spectrum (ES) MH⁺=468.

Example 73

3-(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazole-5-carbonyl)-benzonitrile

This compound was prepared from the resin-bound thiourea of Example 23Fand 2-bromo-1-(3-cyanophenyl)ethanone (which can be prepared by theprocedure of Aloup, J. C. et al., WO 9512594 A1 19950511) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=463.

Example 74

(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-nitro-phenyl)-methanone

This compound was prepared from the resin-bound thiourea of Example 23Fand 2-bromo-1-(3-nitrophenyl)ethanone (which is available from Aldrich)by the procedure used in Example 27. Mass spectrum (ES) MH⁺=483.

Example 75

(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-m-tolyl-methanone

This compound was prepared from the resin-bound thiourea of Example 23Fand 2-bromo-1-(3-methylphenyl)ethanone (which can be prepared by theprocedure of Itoh, T. et al. EP 1020426) by the procedure used inExample 27. Mass spectrum (ES) MH⁺=452.

Example 76

(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-ethyl-phenyl)-methanone

This compound was prepared from the resin-bound thiourea of Example 23Fand 2-bromo-1-(3-ethylphenyl)ethanone (of Example 14O) by the procedureused in Example 27. Mass spectrum (ES) MH⁺=466.

Example 77

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-ethyl-phenyl)-methanone

This compound was prepared from the resin-bound thiourea of Example 18and 2-bromo-1-(3-ethylphenyl)ethanone (of Example 140) by the procedureused in Example 27. Mass spectrum (ES) MH⁺=422.

Example 78

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-m-tolyl-methanone

This compound was prepared from the resin-bound thiourea of Example 18and 2-bromo-1-(3-methylphenyl)ethanone (which can be prepared by theprocedure of Itoh, T. et al. EP 1020426) by the procedure used inExample 27. Mass spectrum (ES) MH⁺=408.

Example 79

3-{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazole-5-carbonyl}-benzonitrile

This compound was prepared from cyanamide,1-(4-isothio-cyanatophenyl)-4-isopropypiperazine (of Example 3) and3-cyanophenacyl bromide (Maybridge Chemical Co. Ltd.) following theprocedure used in Example 24. Mass spectrum (ES) MH⁺=447.

Example 80

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yI}-(3-fluoro-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-(3-fluoro-phenyl)ethanone (Aldrich) by the procedure usedin Example 27. Mass spectrum (ES) MH⁺=440.

Example 81

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3,4,5-trifluoro-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-(3,4,5-trifluoro-phenyl)ethanone (of Example 14H) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=476.

Example 82

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3,5-difluoro-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-(3,5-difluorophenyl)ethanone (of Example 14A) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=458.

Example 83

4-Amino-2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yI]-phenylamino}-thiazol-5-yl)-(3-fluoro-4-methoxy-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 23Band 2-bromo-1-(3-fluoro-4-methoxy-phenyl)ethanone (of Example 13) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=486.

Example 84

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(4-fluoro-3-methoxy-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-(4-fluoro-3-methoxy-phenyl)ethanone (of Example 141) bythe procedure used in Example 27. Mass spectrum (ES) MH⁺=470.

Example 85

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-4-methoxy-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-(3-fluoro-4-methoxy-phenyl)ethanone (of Example 13) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=470.

Example 86

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(4-difluoromethoxy-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-(4-difluoromethoxy-phenyl)ethanone (Maybridge ChemicalCompany Ltd.) by the procedure used in Example 27. Mass spectrum (ES)MH⁺=488.

Example 87

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-trifluoromethoxy-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-(3-trifluoromethoxy-phenyl)ethanone (of Example 14J) bythe procedure used in Example 27. Mass spectrum (ES) MH⁺=506.

Example 88

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(4-piperidin-1-yl-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-(4-piperidin-1-y-phenyl)ethanone (of Example 7) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=505.

Example 89

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(4-morpholin-4-yl-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-(4-morpholin-4-phenyl)ethanone (of Example 8) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=507.

Example 90

(4-Amino-2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3,5-difluoro-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 23Band 2-bromo-1-(3,5-difluorophenyl)ethanone (of Example 14A) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=474.

Example 91

(4-Amino-2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3,4-difluoro-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 23Band 2-bromo-1-(3,4-difluorophenyl)ethanone (Maybridge Chem Co. Ltd.) bythe procedure used in Example 27. Mass spectrum (ES) MH⁺=474.

Example 92

(4-Amino-2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-methoxy-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 23Band 2-bromo-1-(3-methoxy)ethanone (Aldrich) by the procedure used inExample 27. Mass spectrum (ES) MH⁺=468.

Example 93

(4-Amino-2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-benzo[1,3]dioxol-5-yl-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 23Band 2-bromo-1-(benzo[1,3]dioxol-5-yl)ethanone (of Example 11) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=482.

Example 94

(4-Amino-2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 23Band 2-bromo-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)ethanone (MaybridgeChem Co. Ltd.) by the procedure used in Example 27. Mass spectrum (ES)MH⁺=496.

Example 95

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3,5-difluoro-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 18and 2-bromo-1-(3,5-difluorophenyl)ethanone (of Example 14A) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=430.

Example 96

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3,5-difluoro-4-methoxy-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 18and 2-bromo-1-(3,5-difluoro-4-methoxy-phenyl)ethanone (of Example 14K)by the procedure used in Example 27. Mass spectrum (ES) MH⁺=460.

Example 97

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(4-fluoro-3-methoxy-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 18and 2-bromo-1-(4-fluoro-3-methoxy-phenyl)ethanone (of Example 14I) bythe procedure used in Example 27. Mass spectrum (ES) MH⁺=442.

Example 98

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-trifluoromethoxy-phenyl)-methanone(with hydrogen bromide)

This compound was prepared from the resin-bound thiourea of Example 18and 2-bromo-1-(3-trifluoromethoxy-phenyl)ethanone (of Example 14J) bythe procedure used in Example 27. Mass spectrum (ES) MH⁺=478.

Example 99

(4-Amino-2-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-fluoro-phenyl)-methanone(with acetic acid)

This compound was prepared from the resin-bound thiourea of Example 22and 2-bromo-1-(3-fluoro-phenyl)ethanone (Aldrich) by the procedure usedin Example 27. The crude product was purified by HPLC as described inExample 28. Mass spectrum (ES) MH⁺=442.

Example 100

[4-Amino-2-(4-piperazin-1-yl-phenylamino)-thiazol-5-yl]-(3,4,5-trifluorophenyl)-methanone(with acetic acid)

This compound was prepared from the resin-bound thiourea of Example 23Aand 2-bromo-1-(3,4,5-trifluoro-phenyl)ethanone (of Example 14H) by theprocedures used in Example 54. The crude product was purified by HPLC asdescribed in Example 28. Mass spectrum (ES) MH⁺=434.

Example 101

[4-Amino-2-(4-piperazin-1-yl-phenylamino)-thiazol-5-yl]-(3,5-difluoro-4-methoxy-phenyl)-methanone(with acetic acid)

This compound was prepared from the resin-bound thiourea of Example 23Aand 2-bromo-1-(3,5-difluoro-4-methoxy-phenyl)ethanone (of Example 14K)by the procedures used in Example 54. The crude product was purified byHPLC as described in Example 28. Mass spectrum (ES) MH⁺=446.

Example 102

[4-Amino-2-(4-piperazin-1-yl-phenylamino)-thiazol-5-yl]-(4-fluoro-3-methoxy-phenyl)-methanone(with acetic acid)

This compound was prepared from the resin-bound thiourea of Example 23Aand 2-bromo-1-(4-fluoro-3-methoxy-phenyl)ethanone (of Example 14I) bythe procedures used in Example 54. The crude product was purified byHPLC as described in Example 28. Mass spectrum (ES) MH⁺=428.

Example 103

[4-Amino-2-(4-piperazin-1-yl-phenylamino)-thiazol-5-yl]-(3-trifluoromethoxy-phenyl)-methanone(with acetic acid)

This compound was prepared from the resin-bound thiourea of Example 23Aand 2-bromo-1-(3-trifluoromethoxy-phenyl)ethanone (of Example 14J) bythe procedures used in Example 54. The crude product was purified byHPLC as described in Example 28. Mass spectrum (ES) MH⁺=464.

Example 104

{4-Amino-2-[4-(4-sec-butyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-phenyl)-methanone

This compound was prepared from the resin-bound thiourea of Example 23Cand 2-bromo-1-(3-fluoro-phenyl)ethanone (Aldrich) by the procedure usedin Example 27. Mass spectrum (ES) MH⁺=454.

Example 105

{4-Amino-2-[4-(4-sec-butyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-benzo[1,3]dioxol-5-yl-methanone

This compound was prepared from the resin-bound thiourea of Example 23Cand 2-bromo-1-(benzo[1,3]dioxol-5-yl)ethanone (of Example 11) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=480.

Example 106

{4-Amino-2-[4-(4-sec-butyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

This compound was prepared from the resin-bound thiourea of Example 23Cand 2-bromo-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)ethanone (MaybridgeChem Co. Ltd.) by the procedure used in Example 27. Mass spectrum (ES)MH⁺=494.

Example 107

{4-Amino-2-[4-(4-cyclopentyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-benzo[1,3]dioxol-5-yl-methanone

This compound was prepared from the resin-bound thiourea of Example 23Dand 2-bromo-1-(benzo[1,3]dioxol-5-yl)ethanone (of Example 11) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=492.

Example 108

{4-Amino-2-[4-(4-cyclopentyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

This compound was prepared from the resin-bound thiourea of Example 23Dand 2-bromo-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)ethanone (MaybridgeChem Co. Ltd) by the procedure used in Example 27. Mass spectrum (ES)MH⁺=506.

Example 109

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-trifluoromethoxy-phenyl)-methanone

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-(3-trifluoromethoxy-phenyl)ethanone (of Example 14J) bythe procedure used in Example 27. Mass spectrum (ES) MH⁺=506.

Example 110

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-phenyl)-methanone

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-(3-fluoro-phenyl)ethanone (Aldrich) by the procedure usedin Example 27. Mass spectrum (ES) MH⁺=440.

Example 111

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-difluoromethoxy-phenyl)-methanone

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-(3-difluoromethoxy-phenyl)ethanone (of Example 14L) by theprocedure used in Example 27. Mass spectrum (ES) MH⁺=488.

Example 112

{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-hydroxy-phenyl)-methanone(with acetic acid)

This compound was prepared from the resin-bound thiourea of Example 20and 2-bromo-1-(3-hydroxy-phenyl)ethanone (of Example 14N) by theprocedure used in Example 27. The crude product was purified by HPLC asdescribed in Example 28. Mass spectrum (ES) MH⁺=438.

Example 113

{4-Amino-2-[4-(4-isobutyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-hydroxy-phenyl)-methanone(with acetic acid)

This compound was prepared from the resin-bound thiourea of Example 23Eand 2-bromo-1-(3-hydroxy-phenyl)ethanone (of Example 14N) by theprocedure used in Example 27. The crude product was purified by HPLC asdescribed in Example 28. Mass spectrum (ES) MH⁺=452.

Example 114

[4-Amino-2-(4-piperazin-1-yl-phenylamino)-thiazol-5-yl]-(3-difluoromethoxy-phenyl)-methanone

This compound was prepared from the resin-bound thiourea of Example 23Aand 2-bromo-1-(3-difluoromethoxy-phenyl)ethanone (of Example 14L) by theprocedures used in Example 54. Mass spectrum (ES) MH⁺=446.

Example 115

{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-difluoromethoxy-phenyl)-methanone

This compound was prepared from cyanamide,1-(4-isothiocyanatophenyl)-4-cyclopropylmethylpiperazine (of Example14G) and 2-bromo-1-(3-difluoro-methoxyphenyl)ethanone (of Example 14L)following the procedure used in Example 24. Mass spectrum (ES) MH⁺=500.

Example 116

{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-methoxy-phenyl)-methanone

This compound was prepared from cyanamide,1-(4-isothiocyanatophenyl)-4-cyclopropylmethylpiperazine (of Example14G) and 2-bromo-1-(3-methoxyphenyl)ethanone (Aldrich) following theprocedure used in Example 24 Mass spectrum (ES) MH⁺=464.

Example 117

{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-benzo[1,3]dioxol-5-yl-methanone

This compound was prepared from cyanamide,1-(4-isothiocyanatophenyl)-4-cyclopropylmethylpiperazine (of Example14G) and 2-bromo-1-(benzo[1,3]dioxol-5-yl)ethanone (of Example 11)following the procedure used in Example 24 Mass spectrum (ES) MH⁺=478.

Example 118

{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone

This compound was prepared from cyanamide,1-(4-isothiocyanatophenyl)-4-cyclopropylmethylpiperazine (of Example14G) and 2-bromo-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)ethanone(Maybridge Chemical Company Ltd.) following the procedure used inExample 24. Mass spectrum (ES) MH⁺=492.

Example 119

{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-4-hydroxy-phenyl)-methanone

This compound was prepared from cyanamide,1-(4-isothiocyanatophenyl)-4-cyclopropylmethylpiperazine (of Example14G) and 2-bromo-1-(3-fluoro-4-hydroxyphenyl)ethanone (of Example 14M)following the procedure used in Example 24. Mass spectrum (ES) MH⁺=468.

Example 120

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-difluoromethoxy-phenyl)-methanone

This compound was prepared from cyanamide,1-(4-isothiocyanatophenyl)-4-methylpiperazine (of Example 1) and2-bromo-1-(3-difluoro-methoxyphenyl)ethanone (of Example 14L) followingthe procedure used in Example 24. Mass spectrum (ES) MH⁺=460.

Example 121

{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-phenyl)-methanone

This compound was prepared from cyanamide1-(4-isothiocyanatphenyl)-4-cyclopropylmethylpiperazine (of Example 14G) and 2-bromo-1-(3-fluorophenyl)ethanone (Aldrich) following theprocedure used in Example 24 Mass spectrum (ES) MH⁺=452.

Example 122

{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-4-methoxy-phenyl)-methanone

This compound was prepared from cyanamide,1-(4-isothiocyanatophenyl)-4-cyclopropylmethylpiperazine (of Example14G) and 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethanone (of Example 13)following the procedure used in Example 24. Mass spectrum (ES) MH⁺=482.

Example 123

{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-hydroxy-phenyl)-methanone

This compound was prepared from cyanamide,1-(4-isothiocyanatophenyl)-4-cyclopropylmethylpiperazine (of Example 1)and 2-bromo-1-(3-hydroxyphenyl)ethanone (of Example 14N) following theprocedure used in Example 24. Mass spectrum (ES) MH⁺=410.

Example 124

3-{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazole-5-carbonyl}-benzonitrile

This compound was prepared from cyanamide,1-(4-isothiocyanatophenyl)-4-methylpiperazine (of Example 1) and3-cyanophenacyl bromide (Maybridge Chemical Co. Ltd.) following theprocedure used in Example 24. Mass spectrum (ES) MH⁺=419.

Example 125 Antiproliferative Activity

The antiproliferative activity of the compounds of the invention isdemonstrated below. These activities indicate that the compounds of thepresent invention are useful in treating cancer, in particular solidtumors such as breast and colon tumors.

Kinase Assays

To determine inhibition of Cdk4, Cdk2 and Cdk1 activity, kinase assayswere conducted using FlashPlate™ assays (NEN™-Life Science Products).FlashPlate assays were performed using recombinant human cyclin B-CDK1,human cyclin E-CDK2 or human cyclin D1-CDK4 complexes. GST-cyclinE(GST-cycE), CDK2, GST-cyclinB (GST-cycB), CDK1, GST-CDK4 and cyclin D1(cycD1) cDNA clones in baculovirus vectors were provided by Dr. W.Harper at the Baylor College of Medicine, Houston, Tex. Proteins wereco-expressed in High Five™ insect cells and the complex was purified onglutathione Sepharose resin (Pharmacia, Piscataway, N.J.) as previouslydescribed (Harper, J. W. et al. Cell 1993, 75, 805-816). A 6×-Histidinetagged truncated form of retinoblastoma (Rb) protein (amino acid386-928) was used as the substrate for the cycD1-CDK4, cycB-CDK1 and thecycE-CDK2 assays (the expression plasmid was provided by Dr. VeronicaSullivan, Department of Molecular Virology, Roche Research Centre,Welwyn Garden City, United Kingdom). The Rb protein is a naturalsubstrate for phosphorylation by CDK4, CDK2 and CDK1 (see Herwig andStrauss Eur. J. Biochem. Vol. 246 (1997) pp.581-601 and the referencescited therein).

The expression of the 62Kd protein was under the control of an IPTGinducible promoter in an M15 E. coli strain. Cells were lysed bysonication and purification was carried out by binding lysates at pH 8.0to a Ni-chelated agarose column pretreated with 1 mM imidazole. Theresin was then washed several times with incrementally decreasing pHbuffers to pH 6.0, and eluted with 500 mM imidazole. Eluted protein wasdialysed against 20 mM HEPES pH 7.5, 30% glycerol, 200 mM NaCl, and 1 mMDTT. Purified Rb fusion protein stocks were quantitated for proteinconcentration, aliquoted, and stored at −70° C.

For all three kinase assays reported herein, 96-well FlashPlates werecoated with Rb protein at 10 μg/ml, using 100 μl per well. Plates wereincubated at 4° C. overnight or at room temperature for 3 hours on ashaker. To control for nonspecific phosphorylation, one row of wells wascoated with 100 μl/well coating buffer (20 mM HEPES, 0.2 M NaCl). Plateswere then washed twice with wash buffer (0.01% Tween 20 inphosphate-buffered saline). Compounds to be tested (“test compounds”)were added to the wells at 5×final concentration. Reactions wereinitiated by immediate addition of 40 μl reaction mix (25 mM HEPES, 20mM MgCl₂, 0.002% Tween 20, 2 mM DTT, 1 μM ATP, 4 nM ³³P-ATP) and asufficient amount of enzyme to give counts that were at least 10-foldabove background. Plates were incubated at room temperature on a shakerfor 30 minutes. Plates were washed four times with the wash buffer,sealed, and counted on the TopCount scintillation counter (PackardInstrument Co., Downers Grove, Ill.]. The percent inhibition of Rbphosphorylation, which is a measure of the inhibition of CDK activity,was determined according to the following formula:${100 \times 1} - \frac{{{test}\quad {compound}} - {nonspecific}}{{total} - {nonspecific}}$

where “test compound” refers to the average counts per minute of thetest duplicates, “nonspecific” refers to the average counts per minutewhen no CyclinD/Cdk4, etc., was added, and “total” refers to the averagecounts per minute when no compound was added. The IC₅₀ value is theconcentration of test compound that reduces by 50% the protein-kinaseinduced incorporation of the radiolabel under the test conditionsdescribed.

The results of the foregoing in vitro experiments are set forth in Table1 below.

The IC₅₀ values are summarized in the Table 1 below.

Cell Based Assays (Tetrazolium Dye Proliferation Assay)

Proliferation was evaluated by the tetrazolium dye assay according tothe procedure of Denizot and Lang (Denizot, F. and Lang, R. J ImmunolMethods 1986, 89, 271-277). The cell line used was HCT116, a colorectalcarcinoma cell line obtained from the American Type Cell CultureCollection (ATCC;

Rockville, Md.). The cells were grown in McCoy's 5A medium supplementedwith 10% FCS and L-glutamine.

Cells were plated at the appropriate seeding density to give logarithmicgrowth over the course of the assay in a 96-well tissue culture plate.Plates were incubated overnight at 37° C. in a humidified incubator with5% CO₂. The next day, test compounds were serially diluted to four timesthe final concentration in the appropriate medium containing 1.2% DMSO.One-fourth final volume of each dilution was added in duplicate to theplates containing cells. The same volume of 1.2% DMSO in medium wasadded to a row of “control wells” such that the final concentration ofDMSO in each well was 0.3%. Wells to which no cells were added served asthe “blank.” Wells to which no inhibitor was added served as “noinhibitor control.” The plates were) returned to the incubator, and atset time points (determined by their growth curves) plates were analyzedas described below.

3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-2H-tetrazolium bromide(thiazolyl blue; MTT; Sigma) was added to each well to yield a finalconcentration of 1 mg/ml. Plates were returned to the incubator for2.5-3 hours at 37° C. The MTT-containing medium was removed and theresulting formazan metabolite was solubilized in 100% ethanol withshaking for 15 minutes at room temperature. Absorbance readings weretaken in a microtiter plate reader (Dynatech and Molecular Devices platereaders were used interchangeably) at a wavelength of 570 nm with a 650nm reference. Percent inhibition (% INH) is calculated by subtractingthe absorbance of the blank well from all wells, then subtracting theratio of the average absorbance of each test duplicate (S_(AVE)) by theaverage of the controls (C_(AVE)) from 1.00. The final number is thenmultiplied by 100 (% INH=(1.00−S_(AVE)/C_(AVE))×100). The concentrationat which 50% inhibition of cell proliferation is obtained (the IC₅₀) isdetermined from the linear regression of a plot of the logarithm of theconcentration versus percent inhibition. The IC₅₀ values are also shownin Table 1 below.

TABLE 1 This table shows the IC₅₀s of compounds of the instant Examplesin CDK4, CDK2, and CDK1 kinase assays, and also the IC₅₀s in thecell-based assays (“MTT”) assay. Example CDK4 CDK2 CDK1 MTT Number IC₅₀(μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) Example 0.02 4.3 2.5 3.9 24 Example0.018 3.5 0.5 3.5 25 Example 0.059 6.2 9 5.6 26 Example 0.004 9.4 20.19.1 27 Example 0.017 22.2 9.2 9.5 28 Example 0.103 9.6 15.9 9.5 29Example 0.053 2.3 2.4 3.6 30 Example 0.026 2.3 0.5 4.1 31 Example 0.089.6 3.9 5.6 32 Example 0.008 6.5 6.1 9.2 33 Example 0.049 6.1 11.7 3.834 Example 0.008 1.8 1.1 1.8 35 Example 0.025 5.4 2.1 2.8 36 Example0.073 6.3 10 6.6 37 Example 0.006 2.6 2.0 1.9 38 Example 0.021 7.9 2.83.6 39 Example 0.014 3.1 1.3 3.0 40 Example 0.015 3.7 2.9 3.0 41 Example0.01 2.9 1.9 1.5 42 Example 0.021 3.4 1.9 1.3 43 Example 0.028 11.9 1.83.8 44 Example 0.025 4.9 5.6 2.9 45 Example 0.014 5.2 3.6 3.6 46 Example0.043 0.9 0.5 2.8 47 Example 0.01 7.1 2.3 13.3 48 Example 0.015 1.5 2.15.3 49 Example 0.03 2.5 5.5 9.3 50 Example 0.02 0.5 0.9 0.9 51 Example0.028 0.7 1.2 2.3 52 Example 0.006 1.3 2.3 2.5 53 Example 0.013 0.2 0.30.7 54 Example 0.05 3.2 4.3 3.8 55 Example 0.014 0.8 1.0 0.8 56 Example0.009 1.9 0.9 2.1 57 Example 0.019 2.4 3.9 3.1 58 Example 0.024 4.4 4.33.9 59 Example 0.017 7.9 5.9 4.9 60 Example 0.012 2.3 3.5 3.9 61 Example0.044 5.9 10 4.4 62 Example 0.025 5.3 5.2 1.3 63 Example 0.009 4.8 3.58.0 64 Example 0.026 7.4 2.2 1.2 65 Example 0.02 3.8 9.6 10.8 66

Example 126

Tablet Formulation Item Ingredients Mg/Tablet 1 Compound A * 5 25 100250 500 750 2 Anhydrous Lactose 103 83 35 19 38 57 3 Croscarmellose 6 68 16 32 48 Sodium 4 Povidone K30 5 5 6 12 24 36 5 Magnesium Stearate 1 11 3 6 9 Total Weight 120 120 150 300 600 900 * Compound A represents acompound of the invention. Manufacturing Procedure: 1. Mix Items 1, 2and 3 in a suitable mixer for 15 minutes. 2. Granulate the powder mixfrom Step 1 with 20% Povidone K30 Solution (Item 4). 3. Dry thegranulation from Step 2 at 50° C. 4. Pass the granulation from Step 3through a suitable milling equipment. 5. Add the Item 5 to the milledgranulation Step 4 and mix for 3 minutes. 6. Compress the granulationfrom Step 5 on a suitable press.

Example 127

Capsule Formulation Item Ingredients mg/Capsule 1 Compound A * 5 25 100250 500 2 Anhydrous Lactose 159 123 148 — — 3 Corn Starch 25 35 40 35 704 Talc 10 15 10 12 24 5 Magnesium Stearate 1 2 2 3 6 Total Fill Weight200 200 300 300 600 * Compound A represents a compound of the invention.Manufacturing Procedure: 1. Mix Items 1, 2 and 3 in a suitable mixer for15 minutes. 2. Add Items 4 & 5 and mix for 3 minutes. 3. Fill into asuitable capsule.

Example 128

Injection Solution/Emulsion Preparation Item Ingredient mg/mL 1 CompoundA * 1 mg 2 PEG 400 10-50 mg 3 Lecithin 20-50 mg 4 Soy Oil 1-5 mg 5Glycerol 8-12 mg 6 Water q.s. 1 mL Compound A represents a compound ofthe invention. Manufacturing Procedure: 1. Dissolve item I in item 2. 2.Add items 3, 4 and 5 to item 6 and mix until dispersed, then homogenize.3. Add the solution from step 1 to the mixture from step 2 andhomogenize until the dispersion is translucent. 4. Sterile filterthrough a 0.2 μm filter and fill into vials.

Example 129

Injection Solution/Emulsion Preparation Item Ingredient mg/mL 1 CompoundA * 1 mg 2 Glycofurol 10-50 mg 3 Lecithin 20-50 mg 4 Soy Oil 1-5 mg 5Glycerol 8-12 mg 6 Water q.s. 1 mL Compound A represents a compound ofthe invention. Manufacturing Procedure: 1. Dissolve item 1 in item 2. 2.Add items 3, 4 and 5 to item 6 and mix until dispersed, then homogenize.3. Add the solution from step 1 to the mixture from step 2 andhomogenize until the dispersion is translucent. 4. Sterile filterthrough a 0.2 μm filter and fill into vials.

While the invention has been illustrated by reference to specific andpreferred embodiments, those skilled in the art will understand thatvariations and modifications may be made through routine experimentationand practice of the invention. Thus, the invention is intended not to belimited by the foregoing description, but to be defined by the appendedclaims and their equivalents.

What is claimed is:
 1. A compound of formula:

or the pharmaceutically acceptable salts or esters thereof, wherein R¹is selected from the group consisting of H, lower alkyl that optionallymay be substituted with a group selected from OR⁶, cycloalkyl, andNR⁷R⁸, cycloalkyl, COR⁹, and SO₂R¹⁰; R² is selected from the groupconsisting of H, F, Cl, and CH₃; R³, R⁴ and R⁵ are each independentlyselected from the group consisting of H, lower alkyl, which optionallymay be substituted with a group selected from OR⁶ and NR⁷R⁸, OR¹¹,NR¹²R¹³, halogen, NO₂, CONR⁶R⁹, NHSO₂R¹⁴, CN S-lower alkyl, OCF₃, andOCHF₂, provided that R³ and R⁴ or R⁴ and R⁵ are not simultaneously—OCH₃, and provided further that R⁴ is not —Cl when R³ or R⁵ is —NO₂; R⁶and R⁹ are independently selected from the group consisting of H, andlower alkyl that optionally may be substituted by OH and halogen; R⁷ andR⁸ are independently selected from the group consisting of H, and loweralkyl that optionally may be substituted by OR⁶, or, alternatively, R⁷is H and R⁸ is OH, or, alternatively, NR⁷R⁸ can optionally form a ringhaving 5-6 ring atoms, said ring atoms comprising, in addition to thenitrogen atom to which R⁷ and R⁸ are bonded, carbon ring atoms, saidcarbon ring atoms optionally being replaced by one or more additionalhetero atoms and said ring atoms being optionally substituted by thegroup consisting of one or more of OR⁶ and lower alkyl which itself maybe optionally substituted by OH; R¹⁰ selected from the group consistingof lower alkyl which optionally may be substituted by one or morechlorine or fluorine, and NH₂; R¹¹ is selected from the group consistingof H, and lower alkyl that optionally may be substituted by OR⁶, COOH,halogen and NR¹⁵R¹⁶; R¹² and R¹³ are independently selected from thegroup consisting of H, lower alkyl that optionally may be substitutedwith a group selected from OR⁶, COOH and NR¹⁵R¹⁶, COR¹⁷, and SO₂R¹⁸,provided that only one of R¹² and R¹³ is COR¹⁷or SO₂R¹⁸, oralternatively NR¹²R¹³ can optionally form a ring having 5-6 ring atoms,said ring atoms comprising, in addition to the nitrogen atom to whichR¹² and R¹³ are bonded, carbon ring atoms, said carbon ring atomsoptionally being replaced by one or more additional hetero atoms andsaid ring atoms being optionally substituted by the group consisting ofone or more of OR⁶ and lower alkyl which itself may be optionallysubstituted by OH; R¹⁴ is lower alkyl; R¹⁵ and R¹⁶ are independentlyselected from the group consisting of H, and lower alkyl that optionallymay be substituted by OH, or alternatively NR¹⁵R¹⁶ can optionally form aring having 5-6 ring atoms, said ring atoms comprising, in addition tothe nitrogen atom to which R¹⁵ and R¹⁶ are bonded, carbon ring atoms,said carbon ring atoms optionally being replaced by one or moreadditional hetero atoms and said ring atoms being optionally substitutedby the group consisting of one or more of OR⁶ and lower alkyl whichitself may be optionally substituted by OH; R¹⁷ is selected from thegroup consisting of H, and lower alkyl which optionally may besubstituted with a group selected from OH, COOH and NR¹⁵R¹⁶; and R¹⁸ islower alkyl.
 2. The compound of claim 1 wherein R¹ is selected from thegroup consisting of H, CH₂CH₂OH, CH₂CH₂CH₂OH, CH3CO—, CH(CH₃)₂,CH₂CH(CH₃)₂, cyclopropylmethyl and CH₃.
 3. The compound of claim 2wherein R¹ is selected from the group consisting of H, methyl,CH₂CH₂CH₂OH and CH(CH₃)₂.
 4. The compound of claim 1 wherein R² isselected from the group consisting of H and fluorine.
 5. The compound ofclaim 4 wherein R² is H.
 6. The compound of claim 2 wherein R² isselected from the group consisting of H and fluorine.
 7. The compound ofclaim 3 wherein R² is H.
 8. The compound of claim 1 wherein R³ isselected from the group consisting of OR¹¹, lower alkyl, NH2, Cl, F, H,OCHF₂ and NO₂.
 9. The compound claim 6 wherein R³ is selected from thegroup consisting of OR¹¹, lower alkyl, NH2, Cl, F, H, OCHF₂ and NO₂. 10.The compound of claim 7 wherein R³ is selected from the group consistingof F, OCH₃ and CH₂CH₃.
 11. The compound of claim 8 wherein R³ isselected from the group consisting of F, OCH₃ and CH₂CH₃.
 12. Thecompound of claim 1 wherein R⁴ is selected from the group consisting ofacetamido, chloro, diethylamino, hydrogen, hydroxy, hydroxy-ethylamino,[1-(hydroxymethyl)-3-methylbutyl]amino, 1-(3-hydroxymethyl)piperidinyl,4-hydroxy-1-piperidinyl, methoxy, 2-methoxyethylamino,2-methyl-1-pyrrolidinyl, morpholino, piperidinyl, pyrrolidinyl.
 13. Thecompound of claim 12 wherein R⁴ is selected from the group consisting ofH and CH₃O—.
 14. The compound of claim 9 wherein R⁴ is selected from thegroup consisting of acetamido, chloro, diethylamino, hydrogen, hydroxy,hydroxy-ethylamino, [1-(hydroxymethyl)-3-methylbutyl]amino,1-(3-hydroxymethyl)piperidinyl, 4-hydroxy-1-piperidinyl, methoxy,2-methoxyethylamino, 2-methyl-1-pyrrolidinyl, morpholino, piperidinyland pyrrolidinyl.
 15. The compound of claim 10, wherein R⁴ is selectedfrom the group consisting of acetamido, chloro, diethylamino, hydrogen,hydroxy, hydroxy-ethylamino, [1-(hydroxymethyl)-3-methylbutyl]amino,1-(3-hydroxymethyl)piperidinyl, 4-hydroxy-1-piperidinyl, methoxy,2-methoxyethylamino, 2-methyl-1-pyrrolidinyl, morpholino, piperidinyland pyrrolidinyl.
 16. The compound of claim 11, wherein R⁴ is selectedfrom the group consisting of acetamido, chloro, diethylamino, hydrogen,hydroxy, hydroxy-ethylamino, [1-(hydroxymethyl)-3-methylbutyl]amino,1-(3-hydroxymethyl)piperidinyl, 4-hydroxy-1-piperidinyl, methoxy,2-methoxyethylamino, 2-methyl-1-pyrrolidinyl, morpholino, piperidinyland pyrrolidinyl.
 17. The compound of claim 1 wherein R⁵ is selectedfrom the group consisting of H and F.
 18. The compound of claim 17wherein R⁵ is F.
 19. A compound selected from the group consisting of:[4-Amino-2-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](3,5-difluorophenyl)methanone,{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3,5-difluoro-phenyl)-methanone,(4-Amino-2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3,5-difluoro-phenyl)-methanone,{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3,5-difluoro-phenyl)-methanone,and[4-Amino-2-(4-piperazin-1-yl-phenylamino)-thiazol-5-yl]-(3,4,5-trifluorophenyl)-methanone.20. The compound of claim 17 wherein R⁵ is H.
 21. The compound of claim1 wherein at least one of R³, R⁴ and R⁵ is halogen.
 22. A compoundselected from the group consisting of:[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3,4-dichlorophenyl)methanone,[4-Amino-2-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](3-fluorophenyl)methanone,[4-Amino-2-[[4-(1-piperazinyl)phenyl]amino]-5-thiazolyl](3-fluorophenyl)methanone,(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-fluro-phenyl)-methanone,{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-phenyl)-methanone,{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3,4,5-trifluoro-phenyl)-methanone,(4-Amino-2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3,4-difluoro-phenyl)-methanone,(4-Amino-2-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-fluoro-phenyl)-methanone,{4-Amino-2-[4-(4-sec-butyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-phenyl)-methanone,{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-phenyl)-methanone,and{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-phenyl)-methanone.23. The compound of claim 1 wherein at least one of R³, R⁴ and R⁵ isselected from the group consisting of OR¹¹, OCF₃, and OCHF₂.
 24. Acompound selected from the group consisting of:[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl]-(4-hydroxyphenyl)methanone,[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](4-methoxyphenyl)methanone,[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3-fluoro-4-methoxyphenyl)methanone,[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3-methoxyphenyl)methanone,[4-Amino-2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3,5-dimethoxyphenyl)methanone,[4-Amino-2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3-methoxyphenyl)methanone,[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](3-methoxyphenyl)methanone,[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](3,5-dimethoxyphenyl)methanone,[4-Amino-2-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](3-methoxyphenyl)methanone,and[4-Amino-2-[[4-(1-piperazinyl)phenyl]amino]-5-thiazolyl](3-fluoro-4-methoxyphenyl)methanone.25. A compound selected from the group consisting of:{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-methoxy-phenyl)-methanone,(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-methoxy-phenyl)-methanone,4-Amino-2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-fluoro-4-methoxy-phenyl)-methanone,{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(4-fluoro-3-methoxy-phenyl)-methanone,{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-4-methoxy-phenyl)-methanone,{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(4-difluoromethoxy-phenyl)-methanone,{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-trifluoromethoxy-phenyl)-methanone,(4-Amino-2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-methoxy-phenyl)-methanone,{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3,5-difluoro-4-methoxy-phenyl)-methanone,and{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(4-fluoro-3-methoxy-phenyl)-methanone.26. A compound selected from the group consisting of:{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-trifluoromethoxy-phenyl)-methanone,[4-Amino-2-(4-piperazin-1-yl-phenylamino)-thiazol-5-yl]-(3,5-difluoro-4-methoxy-phenyl)-methanone,[4-Amino-2-(4-piperazin-1-yl-phenylamino)-thiazol-5-yl]-(4-fluoro-3-methoxy-phenyl)-methanone,[4-Amino-2-(4-piperazin-1-yl-phenylamino)-thiazol-5-yl]-(3-trifluoromethoxy-phenyl)-methanone,{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-trifluoromethoxy-phenyl)-methanone,{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-difluoromethoxy-phenyl)-methanone,{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-hydroxy-phenyl)-methanone,{4-Amino-2-[4-(4-isobutyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-hydroxy-phenyl)-methanone,[4-Amino-2-(4-piperazin-1-yl-phenylamino)-thiazol-5-yl]-(3-difluoromethoxy-phenyl)-methanone,{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-difluoromethoxy-phenyl)-methanone,{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-methoxy-phenyl)-methanone,{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-4-hydroxy-phenyl)-methanone,{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-difluoromethoxy-phenyl)-methanone,{4-Amino-2-[4-(4-cyclopropylmethyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-fluoro-4-methoxy-phenyl)-methanone,and{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-hydroxy-phenyl)-methanone.27. The compound of claim 1 wherein each of R³, R⁴ and R⁵ isindependently selected from H, NO₂, NHSO₂R⁴ and NR¹²R¹³.
 28. A compoundselected from the group consisting of:[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(1-pyrrolidinyl)phenyl]methanone,[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(1-piperidinyl)phenyl]methanone,[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(4-morpholinyl)phenyl]methanone,acetate salt,[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](3-nitrophenyl)methanone,[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(diethylamino)phenyl]methanone,N-[4-[[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl]carbonyl]phenyl]acetamide,[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl][4-(diethylamino)phenyl]methanone,1-Acetyl-4-[4-[[4-amino-5-[4-(diethylamino)benzoyl]-2-thiazolyl]amino]phenyl]piperazine,trifluoroacetate salt,[4-Amino-2-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl][4-(1-pyrrolidinyl)phenyl]methanone,[4-Amino-2-[[4-(1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(1-pyrrolidinyl)phenyl]methanone, and[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(2-hydroxyethyl)amino-3-nitrophenyl]methanone.29. A compound selected from the group consisting of:[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-(1-pyrrolidinyl)phenyl]methanone,[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-(4-morpholinyl)phenyl]methanone,[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-[(2-methoxyethyl)amino]phenyl]methanone,racemic[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-[3-(hydroxymethyl)-1-piperidinyl]phenyl]methanone,racemic[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-(2-methyl-1-pyrrolidinyl)phenyl]methanone,(R)-[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-[[1-(hydroxymethyl)-3-methylbutyl]amino]phenyl]methanone,[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-nitro-4-(4-hydroxy-1-piperidinyl)phenyl]methanone,[4-Amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][3-amino-4-(4-pyrrolidinyl)phenyl]methanone,and(R)-[3-Amino-4-[[1-(hydroxymethyl)-3-methylbutyl]amino]phenyl][4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl]methanone.30. A compound selected from the group consisting of:[4-Amino-2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl][4-(1-pyrrolidinyl)phenyl]methanone,(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-nitro-phenyl)-methanone,{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(4-piperidin-1-yl-phenyl)-methanone,and{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(4-morpholin-4-yl-phenyl)-methanone.31. The compound of claim 1 wherein any one or more of R³, R⁴ and R⁵ isCN.
 32. A compound selected from the group consisting of:3-(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazole-5-carbonyl)-benzonitrile,3-{4-Amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-thiazole-5-carbonyl}-benzonitrile,and3-{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazole-5-carbonyl}-benzonitrile.33. The compound of claim 1 wherein each one of R³, R⁴ and R⁵ isindependently selected from H and lower alkyl.
 34. A compound selectedfrom the group consisting of:(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-m-tolyl-methanone,(4-Amino-2-{4-[4-(3-hydroxy-propyl)-piperazin-1-yl]-phenylamino}-thiazol-5-yl)-(3-ethyl-phenyl)-methanone,{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-(3-ethyl-phenyl)-methanone,and{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}-m-tolyl-methanone.35. The compound of claim 1 wherein at least one of R³, R⁴ and R⁵ isselected from S-lower akyl.
 36. The compound of claim 35 which is{4-Amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-thiazol-5-yl}(3-methylsulfanyl-phenyl)-methanone.37. The compound[4-Amino-2-[[4-[4-(1-methylethyl)-1-piperazinyl]phenyl]amino]-5-thiazolyl](3-methoxyphenyl)methanone.38. A compound of formula:

or the pharmaceutically acceptable salts or esters thereof, wherein R¹is selected from the group consisting of H, and lower alkyl thatoptionally may be substituted by OR⁶; R² is selected from the groupconsisting of H and F; R³ is selected from the group consisting of H,lower alkyl halogen, NR¹²R¹³, NO₂, OCHF₂, and OR¹¹; R⁴ is selected fromthe group consisting of H, lower alkyl that optionally may be may besubstituted by OR⁶, halogen, NR¹²R¹³, provided that R⁴ is not —Cl whenR³ is —NO₂; R⁵ is selected from the group consisting of H, OR¹¹, and F;R⁶ is selected from the group consisting of H, and methyl; R¹¹ isselected from the group consisting of H, and lower alkyl that optionallymay be substituted by a group selected from OR⁶, COOH, halogen andNR¹⁵R¹⁶; R¹² and R¹³ are independently selected from the groupconsisting of H, lower alkyl that optionally may be substituted with agroup selected from OR⁶, COOH and NR¹⁵R¹⁶, or alternatively NR¹²R¹³ canoptionally form a ring having 5-6 ring atoms, said ring atomscomprising, in addition to the nitrogen atom to which R¹² and R¹³ arebonded, carbon ring atoms, said carbon ring atoms optionally beingreplaced by one or more additional hetero atoms and said ring atomsbeing optionally substituted by the group consisting of one or more ofOR⁶ and lower alkyl which itself may be optionally substituted by OH;and R¹⁵ and R¹⁶ are independently selected from the group consisting ofH, and lower alkyl that optionally may be substituted by OH, oralternatively NR¹⁵R¹⁶ can optionally form a ring having 5-6 ring atoms,said ring atoms comprising, in addition to the nitrogen atom to whichR¹⁵ and R¹⁶ are bonded, carbon ring atoms, said carbon ring atomsoptionally being replaced by one or more additional hetero atoms andsaid ring atoms being optionally substituted by the group consisting ofone or more of OR⁶ and lower alkyl which itself may be optionallysubstituted by OH.
 39. A compound of formula:

or the pharmaceutically acceptable salts or esters thereof, wherein R¹is selected from the group consisting of H, CH₂CH₂OH, CH₂CH₂CH₂OH,CH₃CO—, CH(CH₃)₂, CH₂CH(CH₃)₂, cyclopropylmethyl, and CH₃; R² isselected from the group consisting of H and F; R³ is selected from thegroup consisting of OR¹¹, lower alkyl, NH₂, Cl, F, H, OCHF₂, and NO₂; R⁴is selected from the group consisting of H, and diethylamino; R⁵ is H;and R¹¹ is unsubstituted lower alkyl.
 40. A compound of formula:

or the pharmaceutically acceptable salts or esters thereof, wherein R¹is selected from the group consisting of H, CH₂CH₂CH₂OH, CH(CH₃)₂, CH₃,and cyclopropylmethyl; R², R⁴ and R⁵ are H; and R³ is selected from thegroup consisting of OCH₃, F, and CH₂CH₃.
 41. A pharmaceuticalcomposition comprising as an active ingredient an effective amount of acompound of claim 1 and a pharmaceutically acceptable carrier orexcipient.
 42. The pharmaceutical composition of claim 41 which issuitable for parenteral administration.
 43. A method of treating breast,colon, lung or prostate cancer comprising administering to a subject inneed of such therapy a therapeutically effective amount of a compoundaccording to claim 1.